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94 results on '"Holm, H"'

1. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies

Author

Kevin Rue-Albrecht, Hannah Sharpe, Matthew A. Jackson, E Collantes, A P Frei, Alistair Easton, Fiona Powrie, M Coles, Christopher D. Buckley, Watts Gfm., Holm H. Uhlig, Simon Travis, Sarah McCuaig, M Brenner, Stephen N. Sansom, R Ravindran, Matthias Friedrich, R Tandon, Moustafa Attar, Ilya Korsunsky, Kevin Wei, T Thomas, F Barone, L Thomas, R S Peres, Samuel J. Bullers, Z Christoforidou, K G Lassen, Alessandra Geremia, Elizabeth H. Mann, Soumya Raychaudhuri, Mathilde Pohin, and D Sathananthan

Subjects
Adult, Male, Stromal cell, Neutrophils, Disease, Vascular Remodeling, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, medicine, Humans, Fibroblast, Aged, business.industry, Receptors, Interleukin-1, General Medicine, Fibroblasts, Middle Aged, medicine.disease, Colitis, Inflammatory Bowel Diseases, digestive system diseases, Blockade, medicine.anatomical_structure, Neutrophil Infiltration, Pharmaceutical Preparations, Immunology, Mucosal immunology, Cytokines, Female, Tumor necrosis factor alpha, Stromal Cells, Chemokines, business, Infiltration (medical), Interleukin-1, Signal Transduction
Abstract

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease., Transcriptomic and histological profiling of gut biopsies from multiple independent cohorts of patients with inflammatory bowel disease identifies distinct histopathological, molecular and cellular features associated with treatment response, providing insights for patient stratification and precision therapy.

Published
2021

2. Cells of the human intestinal tract mapped across space and time

Author

Cecilia Domínguez Conde, Ni Huang, Omer Ali Bayraktar, Krishnaa T. Mahbubani, Holm H. Uhlig, Justin Engelbert, Steven Leonard, Emma Dann, Minal Patel, Aaron M. Fleming, Sara F. Vieira, C. Elizabeth Hook, Sarah A. Teichmann, Lia S. Campos, Emily Stephenson, Issac Goh Kai’En, Sophie Pritchard, Stijn van Dongen, Michael D Morgan, Kourosh Saeb-Parsy, Krzysztof Polanski, Rasa Elmentaite, Kenny Roberts, John C. Marioni, Thomas R. W. Oliver, Natsuhiko Kumasaka, Matthias Zilbauer, Roger A. Barker, Francesca Perrone, Kylie R. James, Kerstin B Meyer, Muzlifah Haniffa, Komal Nayak, Menna R. Clatworthy, Vitalii Kleshchevnikov, Steven Lisgo, Liam Bolt, Lira Mamanova, Xiaoling He, Monika Dabrowska, Rachel A. Botting, Matilda Katan, Hamish W King, Elmentaite, Rasa [0000-0001-7366-5466], Kumasaka, Natsuhiko [0000-0002-3557-0375], Roberts, Kenny [0000-0001-6155-0821], Dann, Emma [0000-0002-7400-7438], King, Hamish W. [0000-0001-5972-8926], Bolt, Liam [0000-0001-7293-0774], Vieira, Sara F. [0000-0002-1021-3021], Mamanova, Lira [0000-0003-1463-8622], Katan, Matilda [0000-0001-9992-8375], Oliver, Thomas R. W. [0000-0003-4306-0102], Domínguez Conde, Cecilia [0000-0002-8684-4655], Botting, Rachel A. [0000-0001-9595-4605], Polanski, Krzysztof [0000-0002-2586-9576], Morgan, Michael D. [0000-0003-0757-0711], Marioni, John C. [0000-0001-9092-0852], Bayraktar, Omer Ali [0000-0001-6055-277X], Meyer, Kerstin B. [0000-0001-5906-1498], Uhlig, Holm H. [0000-0002-6111-7355], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Zilbauer, Matthias [0000-0002-7272-0547], Haniffa, Muzlifah [0000-0002-3927-2084], James, Kylie R. [0000-0002-7107-0650], Teichmann, Sarah A. [0000-0002-6294-6366], Apollo - University of Cambridge Repository, King, Hamish W [0000-0001-5972-8926], Vieira, Sara F [0000-0002-1021-3021], Oliver, Thomas RW [0000-0003-4306-0102], Botting, Rachel A [0000-0001-9595-4605], Morgan, Michael D [0000-0003-0757-0711], Marioni, John C [0000-0001-9092-0852], Meyer, Kerstin B [0000-0001-5906-1498], Uhlig, Holm H [0000-0002-6111-7355], Mahbubani, Krishnaa T [0000-0002-1327-2334], James, Kylie R [0000-0002-7107-0650], Teichmann, Sarah A [0000-0002-6294-6366], and Oliver, Thomas R W [0000-0003-4306-0102]

Subjects
Aging, Time Factors, Organogenesis, Cell, Datasets as Topic, Inflammatory bowel disease, 14, Enteric Nervous System, Mice, Crohn Disease, Child, 631/114/2391, health care economics and organizations, Crohn's disease, Multidisciplinary, article, humanities, Cell biology, Intestines, medicine.anatomical_structure, Health, Female, 38/39, medicine.symptom, 631/136, Signal Transduction, Adult, Cellular signalling networks, education, Inflammation, Biology, 38/91, 14/32, Immune system, Fetus, Spatio-Temporal Analysis, 692/699/1503/257/1402, Developmental biology, medicine, Animals, Humans, 45, Receptors, IgG, Epithelial Cells, medicine.disease, Embryonic stem cell, Gastrointestinal Microbiome, Mice, Inbred C57BL, Metagenome, Enteric nervous system, Lymph Nodes
Abstract

Funder: Medical Research Council, The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

Published
2021
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3. Predictive Prenatal Diagnosis for Infantile-onset Inflammatory Bowel Disease Because of Interleukin-10 Signalling Defects

Author

I Williams, Ruth Horn, Daniel Kotlarz, Ying Huang, Galina Ling, Holm H. Uhlig, Alexio M. Muise, Y Zhang, L. de Ridder, Scott B. Snapper, Dror S. Shouval, Kyung Mo Kim, Hirokazu Kanegane, B Wu, C Lei, Z Ye, Christoph Klein, W Hu, Baruch Yerushalmi, Neil Shah, and Pediatrics

Subjects
Pediatrics, medicine.medical_specialty, medicine.medical_treatment, MEDLINE, Prenatal diagnosis, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, 030225 pediatrics, medicine, Humans, Age of Onset, Child, Retrospective Studies, Genetic testing, Fetus, In vitro fertilisation, medicine.diagnostic_test, business.industry, Gastroenterology, Inflammatory Bowel Diseases, medicine.disease, Interleukin-10, Interleukin 10, Pediatrics, Perinatology and Child Health, Amniocentesis, Female, 030211 gastroenterology & hepatology, business
Abstract

OBJECTIVES: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL10 signalling defects due to pathogenic variants in IL10RA, Il10RB and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilisation of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across four countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in one foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.

Published
2021
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4. Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center

Author

Dermot P.B. McGovern, Iram Siddiqui, Claudia Gonzaga-Jauregui, Aleixo M. Muise, Jamie Hu, Michael Brudno, Peter C Church, Scott B. Snapper, Dalin Li, Shiqi Zhang, Andrew D. Paterson, Jie Pan, Daniel Kotlarz, Anne M. Griffiths, Sam Khalouei, Dana M. Bronte-Tinkew, Karoline Fiedler, Chaim M. Roifman, Holm H. Uhlig, Thomas D. Walters, Eileen Crowley, Christoph Klein, Justin Foong, David Tian, Julie E. Horowitz, Abdul Elkadri, Donna A. Wall, Andrei L. Turinsky, Neil Warner, Julia Upton, and Arun K. Ramani

Subjects
Male, 0301 basic medicine, Pediatrics, Inflammatory bowel disease, Whole Exome Sequencing, 0302 clinical medicine, Crohn Disease, Risk Factors, Prevalence, genetics, Family history, Child, Exome sequencing, Ontario, Crohn's disease, Age Factors, Hematopoietic Stem Cell Transplantation, Gastroenterology, Ulcerative colitis, Phenotype, Treatment Outcome, risk factor, Child, Preschool, HSCT, loci, epidemiology, Female, 030211 gastroenterology & hepatology, medicine.medical_specialty, Adolescent, prevalence, Risk Assessment, Article, 03 medical and health sciences, Internal medicine, Exome Sequencing, genomics, medicine, Humans, Transplantation, Homologous, Genetic Predisposition to Disease, Risk factor, Biological Products, Hepatology, business.industry, Infant, Newborn, Genetic Variation, Infant, Odds ratio, mutations, medicine.disease, digestive system diseases, 030104 developmental biology, enteropathy, Colitis, Ulcerative, Age of onset, business
Abstract

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD. Methods: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0–18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses. Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6–18 years. Of the 17 patients with monogenic Crohn’s disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation. Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.

Published
2020
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5. Inflammatory Bowel Disease in Patients with Congenital Chloride Diarrhoea

Author

Ritva Koskela, Jennifer Hollis, Frank M. Ruemmele, Giuseppe Castaldo, Lorenzo Norsa, Giusi Grimaldi, Emeline Bequet, Peter Heinz-Erian, Holm H. Uhlig, Saara Leskinen, Remi Duclaux-Loras, Simon Travis, Alain Lachaux, Roberto Berni Canani, Kaija-Leena Kolho, Astor Rodrigues, Lukasz Dembinski, Jaques Deflandre, Neil Shah, Richard K. Russell, Andreas R. Janecke, Satu Wedenoja, Jutta Köglmeier, Sibylle Koletzko, Norsa, Lorenzo, Berni Canani, Roberto, Duclaux-Loras, Remi, Bequet, Emeline, Köglmeier, Jutta, Russell, Richard K, Uhlig, Holm H, Travis, Simon, Hollis, Jennifer, Koletzko, Sibylle, Grimaldi, Giusi, Castaldo, Giuseppe, Rodrigues, Astor, Deflandre, Jaque, Dembinski, Lukasz, Shah, Neil, Heinz-Erian, Peter, Janecke, Andrea, Leskinen, Saara, Wedenoja, Satu, Koskela, Ritva, Lachaux, Alain, Kolho, Kaija-Leena, Ruemmele, Frank M, HUS Gynecology and Obstetrics, University of Helsinki, Department of Obstetrics and Gynecology, Clinicum, Children's Hospital, and HUS Children and Adolescents

Subjects
Crohn’s disease, Male, medicine.medical_treatment, Gastroenterology, Inflammatory bowel disease, Cohort Studies, 0302 clinical medicine, Prevalence, Chloride-Bicarbonate Antiporters, Child, TUMOR-NECROSIS-FACTOR, Colectomy, 0303 health sciences, Crohn's disease, biology, General Medicine, congenital chloride diarrhoea, Ulcerative colitis, 3. Good health, Europe, Sulfate Transporters, 030211 gastroenterology & hepatology, Female, congenital chloride diarrhea, COLITIS, medicine.drug, Adult, Diarrhea, medicine.medical_specialty, Congenital chloride diarrhea, Adolescent, SLC26A3, ALKALOSIS, Vedolizumab, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, 030304 developmental biology, ulcerative colitis, MUTATIONS, business.industry, medicine.disease, Inflammatory Bowel Diseases, GENE, DRA, digestive system diseases, Infliximab, ADENOMA, MICE, 3121 General medicine, internal medicine and other clinical medicine, Mutation, biology.protein, monogenic disease, REDUCES EXPRESSION, business, Metabolism, Inborn Errors
Abstract

Background Congenital chloride diarrhoea [CLD] is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 [SLC26A3] gene. Patients suffer from life-long watery diarrhoea and chloride loss. Inflammatory bowel disease [IBD] has been reported in individual patients with CLD and in scl26a3-deficient mice. Methods We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD. Results In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients [17%] diagnosed with IBD. Nine patients had Crohn’s disease, two ulcerative colitis and one IBD-unclassified [IBD-U]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5–23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 12 patients had required surgery [ileostomy formation n = 2, ileocaecal resection due to ileocaecal valve stenosis n = 1 and colectomy due to stage II transverse colon cancer n = 1]. At last follow-up, 5/12 were on biologics [adalimumab, infliximab or vedolizumab], 5/12 on immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. Conclusions A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

Published
2021

6. Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Author

Olivia Wenger, Matteo P. Ferla, Ilka Warshawsky, Martin Munteanu, Cas Simons, Matthew Wakeling, Claire G. Salter, Joshua A. Lees, Bernice Lo, Pietro De Camilli, Emma L. Baple, Sara Van Meerbeke, G. Christoph Korenke, Frederico Zara, Barry A. Chioza, Catherine Ward Melver, Manish J. Butte, M. Traverso, Henry Taylor, Marjo S. van der Knaap, Andrew H. Crosby, Matthew Keisling, Joseph S Leslie, Christin Deal, James Fasham, Helen Cox, Ethan M. Scott, Guy Helman, Amber J. McCartney, Yiying Cai, Mamoun Elawad, Tamas Marton, Nicole I. Wolf, Dirk Holzinger, Harold E. Cross, Holm H. Uhlig, Deyana Valcheva, Tamas Balla, Urania Kotzaeridou, Joanna Crawford, Andrea Accogoli, Utkucan Acar, Stephan Tippelt, Dimitris P. Agamanolis, Catherine Walsh Vockley, Pediatric surgery, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
Male, Cell type, Primary Immunodeficiency Diseases, Medizin, Intestinal Atresia, Disease, hypomyelinating leukodystrophy, Biology, Inflammatory bowel disease, Polymorphism, Single Nucleotide, Minor Histocompatibility Antigens, chemistry.chemical_compound, medicine, Humans, Phosphatidylinositol, multiple intestinal atresia, Immunodeficiency, Genetics, Kinase, AcademicSubjects/SCI01870, Original Articles, medicine.disease, Phenotype, Pedigree, FAM126A, Hereditary Central Nervous System Demyelinating Diseases, Phosphotransferases (Alcohol Group Acceptor), TTC7A, chemistry, Female, AcademicSubjects/MED00310, Neurology (clinical), PI4KA
Abstract

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex., Salter et al. show that biallelic variants in PI4KA—which encodes the enzymatic core of the PI4KIIIα-TTC7-FAM126 complex—cause a clinically diverse disorder comprising neurological, intestinal and immunological abnormalities.

Published
2021
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7. Paneth cell dysfunction and the intestinal microbiome in XIAP deficiency

Author

Holm H. Uhlig and Aline Azabdaftari

Subjects
Paneth Cells, business.industry, Immunology, Genetic Diseases, X-Linked, Intestinal dysbiosis, General Medicine, medicine.disease, Inflammatory bowel disease, Lymphoproliferative Disorders, Gastrointestinal Microbiome, medicine.anatomical_structure, Intestinal Microbiome, Paneth cell, Related research, medicine, In patient, XIAP Deficiency, business
Abstract

New data suggest how epithelial dysfunction and intestinal dysbiosis contribute to inflammatory bowel disease in patients and in models of XIAP deficiency (see the related Research Articles by Strigli et al . and Wahida et al . ).

Published
2021
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8. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Serra, Eva Gonçalves, Schwerd, Tobias, Moutsianas, Loukas, Cavounidis, Athena, Fachal, Laura, Pandey, Sumeet, Kammermeier, Jochen, Croft, Nicholas M, Posovszky, Carsten, Rodrigues, Astor, Russell, Richard K, Barakat, Farah, Auth, Marcus K H, Heuschkel, Robert, Zilbauer, Matthias, Fyderek, Krzysztof, Braegger, Christian, Travis, Simon P, Satsangi, Jack, Parkes, Miles, Thapar, Nikhil, Ferry, Helen, Matte, Julie C, Gilmour, Kimberly C, Wedrychowicz, Andrzej, Sullivan, Peter, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem, Roberts, David, Danesh, John, Baeumler, Toni A, Fulga, Tudor A, Karaminejadranjbar, Mohammad, Ahmed, Ahmed, Wilson, Rachel, Barrett, Jeffrey C, Elkadri, Abdul, Griffiths, Anne M, Snapper, Scott B, Shah, Neil, Muise, Aleixo M, Wilson, David C, Uhlig, Holm H, Anderson, Carl A, Marlen, Zurek, Caterina, Strisciuglio, Mamoun, Elawad, Bernice, Lo, Carolina, Arancibia-Carcamo, Adam, Bailey, Ellie, Barnes, Elizabeth Louise, Bird-Lieberman, Oliver, Brain, Barbara, Braden, Jane, Collier, James, East, Lucy, Howarth, Satish, Keshav, Paul, Klenerman, Simon, Leedham, Rebecca, Palmer, Fiona, Powrie, Alison, Simmons, Matthew, Walker, Zoe, Tolkien, Stephen, Kaptoge, David, Allen, Susan, Mehenny, Jonathan, Mant, Emanuele, Di Angelantonio, Simon G, Thompson, Bahtiyar, Yilmaz, Pascal, Juillerat, Markus, Geuking, Reiner, Wiest, Andrew J, Macpherson, Francisco Damian, Bravo, Lukas, Brügger, Ove, Carstens, Ulrike Graf, Bigler, Benjamin, Heimgartner, Monica, Rusticeanu, Sybille, Schmid-Uebelhart, Bruno, Strebel, Aurora, Tatu, Radu, Tutuian, Ove, Øyås, Charlotte, Ramon, Jörg, Stelling, Yannick, Franc, Nicolas, Fournier, Valerie E H, Pittet, Bernard, Burnand, Mara, Egger, Delphine, Golay, Astrid, Marot, Leilla, Musso, Valérie, Pittet, Jean-Benoît, Rossel, Vivianne, Seematter, Joachim, Sommer, Rachel, Vulliamy, Pierre, Michetti, Michel H, Maillard, Céline, Keller, Andreas, Nydegger, Alain, Schoepfe, Eva, Archanioti, Jessica, Ezri, Montserrat, Fraga, Alain, Schoepfer, Christoph, Müller, Gerhard, Rogler, Luc, Biedermann, Mirjam, Blattmann, Sabine, Burk, Barbara, Dora, Michael, Fried, Benjamin, Misselwitz, Beat, Müllhaupt, Nicole, Obialo, Daniel, Pohl, Nadia, Raschle, Michael, Scharl, Stephan, Vavricka, Roland, Von Känel, Jonas, Zeitz, Karim, Abdelrahman, Gentiana, Ademi, Jan, Borovicka, Stephan, Brand, Remus, Frei, Johannes, Haarer, Christina, Knellwolf-Grieger, Claudia, Krieger-Grübel, Patrizia, Künzler, Christa, Meyenberger, Pamela, Meyer, Nina, Röhrich, Mikael, Sawatzki, Martin, Schelling, Gian-Marco, Semadeni, Michael, Sulz, Dorothee, Zimmermann, Patrick, Aepli, Dominique H, Criblez, Cyrill, Hess, Jean-Pierre, Richterich, Johannes, Spalinger, Dominic, Staudenmann, Andreas, Stulz, Stefanie, Wöhrle, Amman, Thomas, Claudia, Anderegg, Henrik, Köhler, Rachel, Kusche, Anca-Teodora, Antonino, Eviano, Arrigoni, José M, Bengoa, Sophie, Cunningham, Philippe, de Saussure, Laurent, Girard, Diana Bakker, de Jong, Polat, Bastürk, Simon, Brunner, Lukas, Degen, Petr, Hruz, Carolina, Khalid-de Bakker, Jan, Niess, Bruno, Balsiger, Janine, Haldemann, Gaby, Saner, Frank, Seibold, Peter, Bauerfeind, Andrea, Becocci, Dominique, Belli, Janek, Binek, Peter, Hengstler, Stephan, Boehm, Tujana, Boldanov, Patrick, Bühr, Rebekka, Koller, Vanessa, Rueger, Arne, Senning, Emanuel, Burri, Sophie, Buyse, Dahlia-Thao, Cao, Fabrizia, D'Angelo, Joakim, Delarive, Christopher, Doerig, Roxane, Hessler, Claudia, Preissler, Ronald, Rentsch, Branislav, Risti, Marc Alain, Ritz, Michael, Steuerwald, Jürg, Vögtlin, Markus, Sagmeister, Bernhard, Sauter, Susanne, Schibli, Christiane, Sokollik, Hugo, Schlauri, Jean-François, Schnegg, Mariam, Seirafi, Holger, Spangenberger, Philippe, Stadler, Peter, Staub, Volker, Stenz, Michela, Tempia-Caliera, Joël, Thorens, Kaspar, Truninger, Patrick, Urfer, Francesco, Viani, Dominique, Vouillamoz, Silvan, Zander, Tina, Wyli, L, Jostins, N A, Kennedy, T, Ahmad, C A, Lamb, C, Edwards, A, Hart, C, Hawkey, J C, Mansfield, C, Mowat, W G, Newman, A, Simmons, M, Tremelling, J C, Lee, N J, Prescott, C G, Mathew, C W, Lees, D P B, McGovern, S R, Targan, G, Botwin, E, Mengesha, P, Fleshner, C, Landers, D, Li, J D, Rioux, A, Bitton, J, Côté-Daigneault, M J, Daly, R, Xavier, K, Morris, G, Boucher, J H, Cho, C, Abraham, M, Merad, B, Sands, I, Peter, K, Hao, Y, Itan, R H, Duerr, L, Konnikova, M B, Schwartz, S, Proksell, E, Johnston, V, Miladinova, W, Chen, S R, Brant, L, Datta, M S, Silverberg, L P, Schumm, S, Birch, M, Giri, K, Gettler, Y, Sharma, C, Stevens, M, Lazarev, T, Haritunians, Fachal, Laura [0000-0002-7256-9752], Croft, Nicholas M [0000-0002-1519-6435], Posovszky, Carsten [0000-0002-9487-8812], Russell, Richard K [0000-0001-7398-4926], Zilbauer, Matthias [0000-0002-7272-0547], Travis, Simon P [0000-0002-2690-4361], Matte, Julie C [0000-0001-5642-648X], Wedrychowicz, Andrzej [0000-0003-1448-167X], Fulga, Tudor A [0000-0002-1056-0082], Karaminejadranjbar, Mohammad [0000-0002-7770-2065], Ahmed, Ahmed [0000-0001-6509-2581], Muise, Aleixo M [0000-0001-9624-3346], Wilson, David C [0000-0003-0879-1129], Apollo - University of Cambridge Repository, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Croft, Nicholas M. [0000-0002-1519-6435], Russell, Richard K. [0000-0001-7398-4926], Travis, Simon P. [0000-0002-2690-4361], Matte, Julie C. [0000-0001-5642-648X], Fulga, Tudor A. [0000-0002-1056-0082], Muise, Aleixo M. [0000-0001-9624-3346], Wilson, David C. [0000-0003-0879-1129], Eva Gonçalves, Serra, Tobias, Schwerd, Loukas, Moutsiana, Athena, Cavounidi, Laura, Fachal, Sumeet, Pandey, Jochen, Kammermeier, Nicholas M, Croft, Carsten, Posovszky, Astor, Rodrigue, Richard K, Russell, Farah, Barakat, Marcus K H, Auth, Robert, Heuschkel, Matthias, Zilbauer, Krzysztof, Fyderek, Christian, Braegger, Simon P, Travi, Jack, Satsangi, Miles, Parke, Nikhil, Thapar, Helen, Ferry, Julie C, Matte, Kimberly C, Gilmour, Andrzej, Wedrychowicz, Peter, Sullivan, Carmel, Moore, Jennifer, Sambrook, Willem, Ouwehand, David, Robert, John, Danesh, Toni A, Baeumler, Tudor A, Fulga, Mohammad, Karaminejadranjbar, Ahmed, Ahmed, Rachel, Wilson, Jeffrey C, Barrett, Abdul, Elkadri, Anne M, Griffith, Scott B, Snapper, Neil, Shah, Aleixo M, Muise, David C, Wilson, Holm H, Uhlig, Carl A, Anderson, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Arancibia-Carcamo, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Elizabeth Louise, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Powrie, Fiona, Simmons, Alison, Walker, Matthew, Tolkien, Zoe, Kaptoge, Stephen, Allen, David, Mehenny, Susan, Mant, Jonathan, Di Angelantonio, Emanuele, Thompson, Simon G, Yilmaz, Bahtiyar, Juillerat, Pascal, Geuking, Marku, Wiest, Reiner, Macpherson, Andrew J, Bravo, Francisco Damian, Brügger, Luka, Carstens, Ove, Bigler, Ulrike Graf, Heimgartner, Benjamin, Rusticeanu, Monica, Schmid-Uebelhart, Sybille, Strebel, Bruno, Tatu, Aurora, Tutuian, Radu, Øyås, Ove, Ramon, Charlotte, Stelling, Jörg, Franc, Yannick, Fournier, Nicola, Pittet, Valerie E H, Burnand, Bernard, Egger, Mara, Golay, Delphine, Marot, Astrid, Musso, Leilla, Pittet, Valérie, Rossel, Jean-Benoît, Seematter, Vivianne, Sommer, Joachim, Vulliamy, Rachel, Michetti, Pierre, Maillard, Michel H, Keller, Céline, Nydegger, Andrea, Schoepfe, Alain, Archanioti, Eva, Ezri, Jessica, Fraga, Montserrat, Schoepfer, Alain, Müller, Christoph, Rogler, Gerhard, Biedermann, Luc, Blattmann, Mirjam, Burk, Sabine, Dora, Barbara, Fried, Michael, Misselwitz, Benjamin, Müllhaupt, Beat, Obialo, Nicole, Pohl, Daniel, Raschle, Nadia, Scharl, Michael, Vavricka, Stephan, Von Känel, Roland, Zeitz, Jona, Abdelrahman, Karim, Ademi, Gentiana, Borovicka, Jan, Brand, Stephan, Frei, Remu, Haarer, Johanne, Knellwolf-Grieger, Christina, Krieger-Grübel, Claudia, Künzler, Patrizia, Meyenberger, Christa, Meyer, Pamela, Röhrich, Nina, Sawatzki, Mikael, Schelling, Martin, Semadeni, Gian-Marco, Sulz, Michael, Zimmermann, Dorothee, Aepli, Patrick, Criblez, Dominique H, Hess, Cyrill, Richterich, Jean-Pierre, Spalinger, Johanne, Staudenmann, Dominic, Stulz, Andrea, Wöhrle, Stefanie, Thomas, Amman, Anderegg, Claudia, Köhler, Henrik, Kusche, Rachel, Antonino, Anca-Teodora, Arrigoni, Eviano, Bengoa, José M, Cunningham, Sophie, de Saussure, Philippe, Girard, Laurent, de Jong, Diana Bakker, Bastürk, Polat, Brunner, Simon, Degen, Luka, Hruz, Petr, Khalid-de Bakker, Carolina, Niess, Jan, Balsiger, Bruno, Haldemann, Janine, Saner, Gaby, Seibold, Frank, Bauerfeind, Peter, Becocci, Andrea, Belli, Dominique, Binek, Janek, Hengstler, Peter, Boehm, Stephan, Boldanov, Tujana, Bühr, Patrick, Koller, Rebekka, Rueger, Vanessa, Senning, Arne, Burri, Emanuel, Buyse, Sophie, Cao, Dahlia-Thao, D'Angelo, Fabrizia, Delarive, Joakim, Doerig, Christopher, Hessler, Roxane, Preissler, Claudia, Rentsch, Ronald, Risti, Branislav, Ritz, Marc Alain, Steuerwald, Michael, Vögtlin, Jürg, Sagmeister, Marku, Sauter, Bernhard, Schibli, Susanne, Sokollik, Christiane, Schlauri, Hugo, Schnegg, Jean-Françoi, Seirafi, Mariam, Spangenberger, Holger, Stadler, Philippe, Staub, Peter, Stenz, Volker, Tempia-Caliera, Michela, Thorens, Joël, Truninger, Kaspar, Urfer, Patrick, Viani, Francesco, Vouillamoz, Dominique, Zander, Silvan, Wyli, Tina, Jostins, L, Kennedy, N A, Ahmad, T, Lamb, C A, Edwards, C, Hart, A, Hawkey, C, Mansfield, J C, Mowat, C, Newman, W G, Simmons, A, Tremelling, M, Lee, J C, Prescott, N J, Mathew, C G, Lees, C W, Mcgovern, D P B, Targan, S R, Botwin, G, Mengesha, E, Fleshner, P, Landers, C, Li, D, Rioux, J D, Bitton, A, Côté-Daigneault, J, Daly, M J, Xavier, R, Morris, K, Boucher, G, Cho, J H, Abraham, C, Merad, M, Sands, B, Peter, I, Hao, K, Itan, Y, Duerr, R H, Konnikova, L, Schwartz, M B, Proksell, S, Johnston, E, Miladinova, V, Chen, W, Brant, S R, Datta, L, Silverberg, M S, Schumm, L P, Birch, S, Giri, M, Gettler, K, Sharma, Y, Stevens, C, Lazarev, M, Haritunians, T, Carrami, Eli M [0000-0002-7770-2065], COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E.L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S.G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A.J., Bravo, F.D., Brügger, L., Carstens, O., Bigler, U.G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Øyås, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, VEH, Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Pittet, V., Rossel, J.B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M.H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Müller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Müllhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Känel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grübel, C., Künzler, P., Meyenberger, C., Meyer, P., Röhrich, N., Sawatzki, M., Schelling, M., Semadeni, G.M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D.H., Hess, C., Richterich, J.P., Spalinger, J., Staudenmann, D., Stulz, A., Wöhrle, S., Thomas, A., Anderegg, C., Köhler, H., Kusche, R., Antonino, A.T., Arrigoni, E., Bengoa, J.M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D.B., Bastürk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C.K., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Bühr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D.T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M.A., Steuerwald, M., Vögtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J.F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N.A., Ahmad, T., Lamb, C.A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J.C., Mowat, C., Newman, W.G., Tremelling, M., Lee, J.C., Prescott, N.J., Mathew, C.G., Lees, C.W., McGovern, DPB, Targan, S.R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J.D., Bitton, A., Côté-Daigneault, J., Daly, M.J., Xavier, R., Morris, K., Boucher, G., Cho, J.H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R.H., Konnikova, L., Schwartz, M.B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S.R., Datta, L., Silverberg, M.S., Schumm, L.P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., and Haritunians, T.

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, 631/208/1516, 13, Inflammatory bowel disease, Whole Exome Sequencing, Adult, Age of Onset, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Female, Genes, Recessive, Genetic Predisposition to Disease, Genetic Variation, Humans, Infant, Infant, Newborn, Inflammatory Bowel Diseases/etiology, Inflammatory Bowel Diseases/genetics, Loss of Function Mutation, Mosaicism, Mutation, NADPH Oxidase 2/genetics, Pedigree, Primary Immunodeficiency Diseases/complications, Primary Immunodeficiency Diseases/genetics, Risk Factors, 0302 clinical medicine, Primary Immunodeficiency Disease, Medicine, lcsh:Science, Exome sequencing, 49/31, education.field_of_study, Multidisciplinary, Medical genetics, article, 692/699/249/1570, 631/250/249/2510/257, 631/208/248, 3. Good health, NADPH Oxidase 2, 030211 gastroenterology & hepatology, Case-Control Studie, Human, medicine.medical_specialty, Science, Primary Immunodeficiency Diseases, Population, 45/22, 45/23, digestive system, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunological deficiency syndromes, Exome Sequencing, Immunogenetics, Allele, education, 45, business.industry, Risk Factor, Inflammatory Bowel Disease, Case-control study, General Chemistry, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, 49, 030104 developmental biology, Immunology, Primary immunodeficiency, lcsh:Q, Age of onset, Cohort Studie, business
Abstract

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P, Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Published
2020
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9. MTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion

Author

Henry Taylor, Marta C. Cohen, Stephan Buderus, Charis Eng, Isabel Rojas, Kevin Sweet, Peter Dale, Natalia Nedelkopoulou, Victor L. Fox, Claudia Phen, Inés Loverdos, Holm H. Uhlig, Tim G. J. de Meij, Jürgen Heise, Isabel Spier, Dilay Yerlioglu, Stefan Aretz, Emmanuel Mas, Veronica Busoni, Mike Thomson, Antje Ballauff, Imperial College London, Istanbul University, University of Texas Southwestern Medical Center [Dallas], Helios Klinikum Krefeld - Helios Klinikum Krefeld, Sheffield Children's NHS Foundation Trust, University Hospital Bonn, University of Barcelona, Italian Hospital of Buenos Aires, Helios Klinikum [Erfurt], Royal Gwent Hospital, Vrije Universiteit Amsterdam [Amsterdam] (VU), Ohio State University [Columbus] (OSU), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Case Western Reserve University [Cleveland], Cleveland Clinic, Gemeinnützige Gesellschaft der Franziskanerinnen zu Olpe mbH (GFO), University of Oxford [Oxford], NIHR Oxford Biomedical Research Centre, Pediatric surgery, Amsterdam Gastroenterology Endocrinology Metabolism, and Amsterdam Reproduction & Development (AR&D)

Subjects
AcademicSubjects/SCI01140, 03 medical and health sciences, 0302 clinical medicine, Neoplastic Syndromes, Hereditary, Genetics, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], PTEN, Humans, Enteropathy, Juvenile polyposis syndrome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Genetics (clinical), PI3K/AKT/mTOR pathway, Bone Morphogenetic Protein Receptors, Type I, Colectomy, 030304 developmental biology, 0303 health sciences, Everolimus, biology, Intestinal Polyposis, TOR Serine-Threonine Kinases, PTEN Phosphohydrolase, General Medicine, MTOR Inhibitors, medicine.disease, BMPR1A, 3. Good health, 030220 oncology & carcinogenesis, Sirolimus, biology.protein, Cancer research, General Article, Haploinsufficiency, Gastrointestinal Hemorrhage, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07–0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase–AKT–mTOR pathway mitigates the detrimental synergistic effects of combined PTEN–BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome., Graphical Abstract Graphical Abstract

Published
2021
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10. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies

Author

Matthew Kowalik, Edward E. S. Nieuwenhuis, Dror S. Shouval, Michael Field, Kaiyue Peng, Hans Clevers, Aleixo M. Muise, Marla Dubinsky, Carmen Argmann, Dermot P.B. McGovern, Scott B. Snapper, Michal Mokry, Christoph Klein, Daniel Kotlarz, Elizabeth A. Spencer, Leslie Grushkin-Lerner, Fiona Powrie, Sung-Yun Pai, Holm H. Uhlig, Eric E. Schadt, Athos Bousvaros, Jodie Ouahed, Judy H. Cho, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
0301 basic medicine, Clinical Review, Pediatrics, medicine.medical_specialty, Primary Immunodeficiency Diseases, Psychological intervention, digestive system, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Age of Onset, business.industry, Incidence (epidemiology), Gastroenterology, Inflammatory Bowel Diseases, medicine.disease, Very early onset, digestive system diseases, Phenotype, 030104 developmental biology, Child, Preschool, Expert opinion, Etiology, 030211 gastroenterology & hepatology, business
Abstract

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

Published
2019
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11. A pilot study on automatic three-dimensional quantification of Barrett's esophagus for risk stratification and therapy monitoring

Author

Bruce George, Maryam Haghighat, Alessandra Geremia, Lucy Howarth, Fiona Powrie, Holm H. Uhlig, James E. East, E Barnes, Jane Collier, Sharib Ali, Paul Klenerman, Alissa Walsh, Kelsey D. J. Jones, Elizabeth L. Bird-Lieberman, Stephen Ash, Astor Rodrigues, Simon J. Leedham, Alison Simmons, Xin Lu, Carolina V Arancibia-Cárcamo, Philip Allan, Jan Bornschein, Simon Travis, Barbara Braden, Tim Ambrose, Rebecca Palmer, Jack Satsangi, Emma L. Culver, Adam A. Bailey, Jens Rittscher, Oliver Brain, and Investigators, TGU

Subjects
Male, 3d printed, Esophageal Mucosa, Endoscope, Pilot Projects, Gastroesophageal Junction, Risk Assessment, Severity of Illness Index, Imaging phantom, Automation, Barrett Esophagus, Deep Learning, Imaging, Three-Dimensional, Predictive Value of Tests, Risk Factors, Image Interpretation, Computer-Assisted, medicine, Humans, Aged, Mathematics, Hepatology, medicine.diagnostic_test, business.industry, Gastroenterology, Reproducibility of Results, medicine.disease, Endoscopy, Treatment Outcome, Barrett's esophagus, Risk stratification, Disease Progression, Female, Therapy monitoring, Esophagogastric Junction, Esophagoscopy, Nuclear medicine, business
Abstract

Background & Aims Barrett’s epithelium measurement using widely accepted Prague C&M classification is highly operator dependent. We propose a novel methodology for measuring this risk score automatically. The method also enables quantification of the area of Barrett’s epithelium (BEA) and islands, which was not possible before. Furthermore, it allows 3-dimensional (3D) reconstruction of the esophageal surface, enabling interactive 3D visualization. We aimed to assess the accuracy of the proposed artificial intelligence system on both phantom and endoscopic patient data. Methods Using advanced deep learning, a depth estimator network is used to predict endoscope camera distance from the gastric folds. By segmenting BEA and gastroesophageal junction and projecting them to the estimated mm distances, we measure C&M scores including the BEA. The derived endoscopy artificial intelligence system was tested on a purpose-built 3D printed esophagus phantom with varying BEAs and on 194 high-definition videos from 131 patients with C&M values scored by expert endoscopists. Results Endoscopic phantom video data demonstrated a 97.2% accuracy with a marginal ± 0.9 mm average deviation for C&M and island measurements, while for BEA we achieved 98.4% accuracy with only ±0.4 cm2 average deviation compared with ground-truth. On patient data, the C&M measurements provided by our system concurred with expert scores with marginal overall relative error (mean difference) of 8% (3.6 mm) and 7% (2.8 mm) for C and M scores, respectively. Conclusions The proposed methodology automatically extracts Prague C&M scores with high accuracy. Quantification and 3D reconstruction of the entire Barrett’s area provides new opportunities for risk stratification and assessment of therapy response.

Published
2021
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12. Cells of the human intestinal tract mapped across space and time

Author

Sarah A. Teichmann, Lia S. Campos, Emma Dann, Sophie Pritchard, K Saeb Parsy, Ni Huang, Justin Engelbert, Sara F. Vieira, Krishnaa T. Mahbubani, Steve Lisgo, Matthias Zilbauer, Minal Patel, Holm H. Uhlig, Morgan, Aaron M. Fleming, Matilda Katan, Hamish W King, Omer Ali Bayraktar, C Dominguez-Conde, Natsuhiko Kumasaka, Clatworthy, Krzysztof Polanski, Francesca Perrone, Rasa Elmentaite, Emily Stephenson, Steven Leonard, S. van Dongen, Kerstin B. Meyer, Komal Nayak, I Goh Kai’En, Kylie R. James, Muzlifah Haniffa, CE Hook, John C. Marioni, Monika Dabrowska, Liam Bolt, Lira Mamanova, Rachel A. Botting, Trw Oliver, and Kenny Roberts

Subjects
Cell type, Cell, Inflammation, Biology, medicine.disease, Inflammatory bowel disease, Cell biology, Pathogenesis, medicine.anatomical_structure, Immune system, medicine, Enteric nervous system, medicine.symptom, Homeostasis
Abstract

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. To comprehensively map cell lineages in the healthy developing, pediatric and adult human gut from ten distinct anatomical regions, as well as draining lymph nodes, we used singlecell RNA-seq and VDJ analysis of roughly one third of a million cells. This reveals the presence of BEST4+ absorptive cells throughout the human intestinal tract, demonstrating the existence of this cell type beyond the colon for the first time. Furthermore, we implicate IgG sensing as a novel function of intestinal tuft cells, and link these cells to the pathogenesis of inflammatory bowel disease. We define novel glial and neuronal cell populations in the developing enteric nervous system, and predict cell-type specific expression of Hirschsprung’s disease-associated genes. Finally, using a systems approach, we identify key cell players across multiple cell lineages driving secondary lymphoid tissue formation in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. These data provide an unprecedented catalogue of intestinal cells, and new insights into cellular programs in development, homeostasis and disease.

Published
2021
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13. IL-1-driven stromal-neutrophil interaction in deep ulcers defines a pathotype of therapy non-responsive inflammatory bowel disease

Author

Kevin Wei, Moustafa Attar, Ilya Korsunsky, T Thomas, Elizabeth H. Mann, Fiona Powrie, Holm H. Uhlig, Sarah McCuaig, Mathilde Pohin, Stephen N. Sansom, R S Peres, Matthias Friedrich, E Collantes, R Ravindran, Alistair Easton, Simon Travis, Kevin Rue-Albrecht, Soumya Raychaudhuri, D Sathananthan, L Thomas, Samuel J. Bullers, Watts Gfm., Z Christoforidou, Hannah Sharpe, Matthew A. Jackson, and Alessandra Geremia

Subjects
Transcriptome, Stromal cell, business.industry, Immunology, medicine, Chemotaxis, Disease, medicine.disease, business, Inflammatory bowel disease, Infiltration (medical), Vascular remodelling in the embryo, Blockade
Abstract

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology, and in situ localisation, we describe heterogeneity of the tissular inflammatory response in IBD treatment failure. Among inflammatory pathotypes, we found high neutrophil infiltration, activation of fibroblasts, and vascular remodelling at sites of deep ulceration was a feature of non-response to several anti-inflammatory therapies. Activated fibroblasts in the ulcer bed display neutrophil chemoattractant properties that are IL-1R- but not TNF-dependent. The identification of distinct, localised, tissular pathotypes associated with treatment non-response will aid precision targeting of current therapeutics and provide a biological rationale for IL-1 signalling blockade in ulcerating disease.

Published
2021
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14. Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

Author

S Ünal, J Koeglmeier, M Meissl, H Ayyıldız Civan, J Melek, T Siahanidou, A M Demir, Patrick Gerner, J H Montoya, Duba H-C., Denise Aldrian, A Koutroumpa, Sahar Mansour, Michael W. Hess, Murat Cakir, Georg F. Vogel, Thomas Müller, J Hornova, T K Frey, Aysel Ünlüsoy Aksu, Y Rachman, Ekkehard Sturm, Andreas R. Janecke, G Düker, M Miqdady, Lukas A. Huber, R Lima, Frank M. Ruemmele, Carsten Posovszky, J Hertecant, Holm H. Uhlig, E Ramos Boluda, Stefan Wirth, Raffi Lev-Tzion, C Deppisch, R Lanzersdorfer, Merit M. Tabbers, Simone Kathemann, Yaron Avitzur, Paediatric Gastroenterology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development

Subjects
Diarrhea, 0301 basic medicine, medicine.medical_specialty, Genetic counseling, Myosin, Medizin, lcsh:Medicine, Disease, Myosins, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, lack of protein, Medicine, Enteropathy, ddc:610, tail domain, Lack of protein, Cholestasis, business.industry, Genotype–phenotype correlation, lcsh:R, Progressive familial intrahepatic cholestasis, General Medicine, genotype–phenotype correlation, Tail domain, medicine.disease, congenital diarrheal diseases, Phenotype, PFIC, Cholestase, Transplantation, Durchfall, 030104 developmental biology, Parenteral nutrition, Kontraktile Proteine, MYO5B, enteropathy, YO5B, 030211 gastroenterology & hepatology, progressive familial intrahepatic cholestasis, business, myosin Vbin, DDC 610 / Medicine & health, myosin Vb, microvillus inclusion disease
Abstract

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling., publishedVersion

Published
2021

15. Immune predictors of oral poliovirus vaccine immunogenicity among infants in South India

Author

Gagandeep Kang, Nithya Jeyavelu, Sidhartha Giri, Srinivasan Venugopal, Saravanakumar Puthupalayam Kaliappan, Nisha Jose, Ira Praharaj, Yin-Huai Chen, Chanduni Syed, Jacob John, Nicholas C. Grassly, Edward P.K. Parker, Holm H. Uhlig, Beate Kampmann, Punithavathy Manickavasagam, Miren Iturriza-Gomara, Sudhir Babji, Bill & Melinda Gates Foundation, and Medical Research Council (MRC)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Live attenuated vaccines, Immunology, CHILDREN, Research & Experimental Medicine, medicine.disease_cause, Paediatric research, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, INFECTION, medicine, Pharmacology (medical), 030212 general & internal medicine, DEVELOPING-COUNTRIES, Seroconversion, HUMAN ROTAVIRUS VACCINE, Pharmacology, Science & Technology, Environmental enteropathy, business.industry, Poliovirus, Immunogenicity, GUT MICROBIOTA, EFFICACY, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, DIARRHEA, 3. Good health, Vaccination, Diarrhea, 030104 developmental biology, Infectious Diseases, Medicine, Research & Experimental, Immunization, VIRUS, TRIAL, medicine.symptom, business, lcsh:RC581-607, Life Sciences & Biomedicine, NEWBORN
Abstract

Identification of the causes of poor oral vaccine immunogenicity in low-income countries might lead to more effective vaccines. We measured mucosal and systemic immune parameters at the time of vaccination with oral poliovirus vaccine (OPV) in 292 Indian infants aged 6–11 months, including plasma cytokines, leukocyte counts, fecal biomarkers of environmental enteropathy and peripheral blood T-cell phenotype, focused on gut-homing regulatory CD4+ populations. We did not find a distinct immune phenotype associated with OPV immunogenicity, although viral pathogens were more prevalent in stool at the time of immunization among infants who failed to seroconvert (63.9% vs. 45.6%, p = 0.002). Using a machine-learning approach, we could predict seroconversion a priori using immune parameters and infection status with a median 58% accuracy (cross-validation IQR: 50–69%) compared with 50% expected by chance. Better identification of immune predictors of OPV immunogenicity is likely to require sampling of mucosal tissue and improved oral poliovirus infection models.

Published
2020

16. Negative regulation ofACE2by interferonsin vivoand its genetic control

Author

J K Baillie, Narayan Ramamurthy, Lin S-K., Dominik Aschenbrenner, Angela Mo, Alexander J. Mentzer, Emanuele Marchi, M A Ansari, Greg Gibson, Eshita Sharma, Hackstein C-P., Suresh Venkateswaran, John A. Todd, Sarah A. Teichmann, Holm H. Uhlig, Subra Kugathasan, Paul Klenerman, Rory Bowden, Eleanor Barnes, V Pedergnana, John McLauchlan, and James C. Knight

Subjects
0303 health sciences, Gastrointestinal tract, Cirrhosis, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, In vivo, Interferon, Liver tissue, Expression quantitative trait loci, Immunology, medicine, Receptor, Gene, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally.ACE2is a receptor for SARS-CoV-2 and differences in expression may affect susceptibility to COVID-19. Using HCV-infected liver tissue from 195 individuals, we discovered that among genes negatively correlated withACE2, interferon signalling pathways were highly enriched and observed down-regulation ofACE2after interferon-alpha treatment. Negative correlation was also found in the gastrointestinal tract and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation ofACE2across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda (IFNL) region are associated withACE2expression. IncreasedACE2expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in theIFNLregion may impact not only antiviral responses but alsoACE2with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.

Published
2020
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17. Oral Vancomycin and Gentamicin for Treatment of Very Early Onset Inflammatory Bowel Disease

Author

Dan Turner, Holm H. Uhlig, Raffi Lev-Tzion, Oren Ledder, Eyal Shteyer, and Michelle Li Nien Tan

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Antibiotics, Administration, Oral, Inflammatory bowel disease, Primary sclerosing cholangitis, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Vancomycin, law, Internal medicine, medicine, Humans, Age of Onset, business.industry, Therapeutic effect, Gastroenterology, Infant, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, Anti-Bacterial Agents, 030104 developmental biology, Child, Preschool, Immunology, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Gentamicin, Anaerobic bacteria, Gentamicins, business, medicine.drug
Abstract

Background: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. Methods: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. Results: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. Conclusion: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits.

Published
2017
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18. Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN

Author

Lisa Richmond, Ron Shaoul, Neil Shah, Dan Turner, Tim G. J. de Meij, Johanna C. Escher, Lissy de Ridder, Amit Assa, Oren Ledder, Victorien M. Wolters, Javier Martín-de-Carpi, Astor Rodrigues, Arie Levine, Carsten Posovszky, Christian Jakobsen, Shlomi Cohen, Mira Friedman, Jiri Bronsky, Kaija-Leena Kolho, Dror S. Shouval, Frank M. Ruemmele, Holm H. Uhlig, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, AGEM - Digestive immunity, AII - Inflammatory diseases, and Pediatrics

Subjects
Male, medicine.medical_specialty, Pediatrics, paediatric, Adolescent, Vedolizumab, medicine.medical_treatment, Antibodies, Monoclonal, Humanized, Inflammatory bowel disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Maintenance therapy, inflammatory bowel disease, Interquartile range, Internal medicine, Journal Article, medicine, Humans, Child, Retrospective Studies, Colectomy, business.industry, General Medicine, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, Treatment Outcome, Child, Preschool, 030220 oncology & carcinogenesis, Concomitant, Cohort, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Background: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method: Retrospective review of children [aged 2–18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results: In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14–38; range 6–116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohn’s disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions: Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

Published
2017
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19. Crohn’s Disease in Niemann–Pick Disease Type C1: Caught in the Cross-Fire of Host-Microbial Interactions

Author

Athena Cavounidis and Holm H. Uhlig

Subjects
0301 basic medicine, medicine.medical_specialty, Crohn's disease, Physiology, Host (biology), business.industry, Gastroenterology, Hepatology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Transplant surgery, Internal medicine, Immunology, medicine, business, 030217 neurology & neurosurgery, Niemann-pick disease type
Published
2018
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20. Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

Author

Mark Coles, Chen Y-H., Simon Travis, Subra Kugathasan, C Arancibia, Dominik Aschenbrenner, Stephen Ho, Boyd Steere, Nicholas E. Ilott, Joanneke E. Jansen, Karen Cox, M Quaranta, Fiona Powrie, Holm H. Uhlig, Jochen Schmitz, Eamonn A. Gaffney, Soumya Banerjee, Lee A. Denson, and Stephen N. Sansom

Subjects
business.industry, Monocyte, Lymphocyte differentiation, Inflammation, medicine.disease, Peripheral blood mononuclear cell, Inflammatory bowel disease, Interleukin 10, Immune system, medicine.anatomical_structure, Immunology, medicine, Interleukin 23, medicine.symptom, business
Abstract

BACKGROUND & AIMSDysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine.METHODSWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples.RESULTSWe characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.CONCLUSIONOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

Published
2019

22. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years

Author

Chiara Bacchelli, Kate Reeve, Marco Gasparetto, Heather Godwin, Suzanne Drury, Nikki Acton, Gabi Noble-Jamieson, S. Chadokufa, Holm H. Uhlig, Chela James, Sara Sider, B. Huggett, Matilde Pescarin, Elena Cernat, Jochen Kammermeier, Neil Shah, Robert Dziubak, PL Beales, Kimberly Gilmour, Neil J. Sebire, Mamoun Elawad, and Fevronia Kiparissi

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Disease, Hematopoietic stem cell transplantation, Inflammatory bowel disease, Gastroenterology, Endoscopy, Gastrointestinal, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Interquartile range, Internal medicine, medicine, Humans, Genetic Testing, Age of Onset, Immunodeficiency, business.industry, Infant, General Medicine, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, digestive system diseases, Intestines, Transplantation, Phenotype, 030104 developmental biology, Immunology, Original Article, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, Age of onset, business
Abstract

Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [ EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A ]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.

Published
2016
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23. Sa1121 COMPOUND HETEROZYGOTE TRIM22 VARIANTS ARE A POTENTIAL MODIFIER OF INFLAMMATORY BOWEL DISEASE THROUGH DEFECTIVE MURAMYL DIPEPTIDE-MEDIATED ANTIMICROBIAL ACTIVITY

Author

Imogen S. Stafford, Tracy Coelho, Sumeet Pandey, R Mark Beattie, Sarah Ennis, Holm H. Uhlig, Enrico Mossotto, and James J. Ashton

Subjects
chemistry.chemical_compound, Hepatology, chemistry, Gastroenterology, medicine, Pharmacology, TRIM22, Compound heterozygosity, medicine.disease, Antimicrobial, Inflammatory bowel disease, Muramyl dipeptide
Published
2020
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24. Defining faecal calprotectin thresholds as a surrogate for endoscopic and histological disease activity in ulcerative colitis - a prospective analysis

Author

Vanashree Sexton, Chris Hinds, Oliver Brain, Simon Travis, Alissa Walsh, Gary S. Collins, Holm H. Uhlig, Satish Keshav, Michele Peters, Guy M. Goodwin, John R. Geddes, and Andrey Kormilitzin

Subjects
0301 basic medicine, medicine.medical_specialty, Colon, Biopsy, Gastroenterology, Severity of Illness Index, 03 medical and health sciences, Feces, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Colitis, Intestinal Mucosa, Receiver operating characteristic, business.industry, Surrogate endpoint, Area under the curve, General Medicine, Colonoscopy, medicine.disease, Faecal calprotectin, Ulcerative colitis, Confidence interval, 030104 developmental biology, ROC Curve, Area Under Curve, 030211 gastroenterology & hepatology, Histopathology, Colitis, Ulcerative, Symptom Assessment, business, Leukocyte L1 Antigen Complex, Biomarkers
Abstract

Background Faecal calprotectin [FCal] levels are used as a surrogate marker for mucosal inflammation, but thresholds for defining endoscopic or histological disease activity in ulcerative colitis [UC] remain unclear. Methods Using validated indices, prospective measurements of FCal, symptoms [Simple Colitis Clinical Activity Index, SCCAI], endoscopic [Ulcerative Colitis Endoscopic Index of Severity, UCEIS] and histological activity [Nancy index] were made over 6 months in patients enrolled into the TrueColours UC web-based monitoring programme. Repeated measurements correlation was performed between FCal and SCCAI, UCEIS, and Nancy indices using definitions for remission and active disease [UCEIS: remission ≤1, active ≥4; Nancy: remission ≤1, active ≥2; combined criteria: remission UCEIS ≤1 and Nancy ≤1, active UCEIS ≥4 and Nancy ≥2]. Receiver operating characteristic curves investigated FCal thresholds after maximising sensitivity for active disease. Results In 39 patients followed prospectively for 6 months, correlation coefficients between FCal and SCCAI, UCEIS, and Nancy indices were 0.271 (95% confidence interval [CI] 0.114–0.415), 0.741 [95% CI 0.289–0.922], and 0.876 [95% CI 0.605–0.965], respectively. Median FCal thresholds for remission using endoscopic, histological, or combined criteria were 71 μg/g [range 8–624], 91 μg/g [range 8–858], and 67 μg/g [range 8–479], respectively. The FCal threshold above which active disease was confirmed was 187 μg/g for UCEIS (area under the curve [AUC] 0.915), 72 μg/g for Nancy [AUC 0.824], and 187 μg/g for combined endoscopic and histological criteria [AUC 0.936]. Conclusions Correlation between FCal and symptoms in UC is weak. In contrast, the correlation between FCal and endoscopic or histological activity is strong. An FCal ≥72 μg/g indicates histological inflammation [Nancy ≥2] and ≥187 μg/g indicates endoscopically active disease [UCEIS ≥4], whether combined with histopathology or not.

Published
2018

25. Consequences of identifying XIAP deficiency in an adult patient with inflammatory bowel disease

Author

M Quaranta, Travis Spl., Tobias Schwerd, Paul Klenerman, Carl A. Anderson, Kimberly Gilmour, E Gonçalves Serra, Satish Keshav, Fiona Powrie, Holm H. Uhlig, R Wilson, and Sumeet Pandey

Subjects
0301 basic medicine, Hepatology, business.industry, Gastroenterology, medicine.disease, digestive system, Phenotype, Inflammatory bowel disease, Very early onset, digestive system diseases, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunology, medicine, 030211 gastroenterology & hepatology, XIAP Deficiency, business
Abstract

In some patients with extreme phenotypes of inflammatory bowel disease (IBD; in particular in those with infantile or very early onset IBD with

Published
2018
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26. Translating immunology into therapeutic concepts for inflammatory bowel disease

Author

Fiona Powrie and Holm H. Uhlig

Subjects
0301 basic medicine, Drug-Related Side Effects and Adverse Reactions, Immunology, Biology, medicine.disease_cause, Inflammatory bowel disease, digestive system, Autoimmunity, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Molecular Targeted Therapy, Epigenetics, Colitis, Innate immune system, business.industry, Disease Management, Inflammatory Bowel Diseases, medicine.disease, Acquired immune system, digestive system diseases, Gastrointestinal Microbiome, Disease Models, Animal, 030104 developmental biology, 030220 oncology & carcinogenesis, Chronic Disease, Dysbiosis, Disease Susceptibility, Personalized medicine, business, Biomarkers
Abstract

Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder–associated IBD increasingly directs treatment strategies as part of personalized medicine.

Published
2018

27. Antibody concentrations decrease 14-fold in children with celiac disease on a gluten-free diet but remain high at 3 months

Author

Thomas Richter, Matthias Heiduk, Johannes Wolf, Dirk Hasenclever, Andreas Krahl, Martin W. Laass, Antje Schmidt, Peter Lauenstein, Almuthe C. Hauer, Norman Händel, Jan de Laffolie, David Petroff, Holm H. Uhlig, Marcus K. H. Auth, Gunter Flemming, and Thomas Mothes

Subjects
Male, Immunoglobulin A, medicine.medical_specialty, Time Factors, Adolescent, Gastroenterology, Coeliac disease, Immunoglobulin G, Serology, Diet, Gluten-Free, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Humans, Prospective Studies, Child, Prospective cohort study, Autoantibodies, Hepatology, biology, business.industry, Infant, medicine.disease, Celiac Disease, Child, Preschool, biology.protein, Female, 030211 gastroenterology & hepatology, Gluten free, Gliadin, business, Body mass index, Blood Chemical Analysis, Follow-Up Studies
Abstract

Background & Aims Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to gluten-free diet are required for optimal treatment. Methods In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later. Results The geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0–16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response. Conclusions Serum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.

Published
2018

28. Corrigendum: Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN

Author

Astor Rodrigues, Tim G. J. de Meij, Johanna C. Escher, Lissy de Ridder, Dan Turner, Ron Shaoul, Shlomi Cohen, Kaija-Leena Kolho, Javier Martín-de-Carpi, Neil Shah, Mira Friedman, Holm H. Uhlig, Oren Ledder, Jiri Bronsky, Lisa Richmond, Dror S. Shouval, Frank M. Ruemmele, Amit Assa, Carsten Posovszky, Christian Jakobsen, Victorien M. Wolters, and Arie Levine

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, Gastroenterology, General Medicine, medicine.disease, Inflammatory bowel disease, 3. Good health, Vedolizumab, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030211 gastroenterology & hepatology, Multi centre, Colitis, business, 030304 developmental biology, medicine.drug
Abstract

In the original article, author Carsten Posovszky's surname was incorrectly spelt. This has now been corrected.

Published
2018

29. Defects in Nicotinamide-adenine Dinucleotide Phosphate Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease

Author

Sandeep S. Dhillon, Billy Bourke, Anne M. Griffiths, Conghui H. Guo, Dermot P.B. McGovern, James H. Doroshow, Inga Peter, Luis Alvarez, Lidija Kovačič, Abdul Elkadri, Scott B. Snapper, Aleixo M. Muise, Ken Y. Hui, Judy H. Cho, Gabriella Aviello, Steven R. Brant, Cornelia Thoeni, Kim O’Neill, Holm H. Uhlig, John H. Brumell, PK Hayes, Ulla G. Knaus, Mark S. Silverberg, Hayes, P., Dhillon, S., O'Neill, K., Thoeni, C., Hui, K. Y., Elkadri, A., Guo, C. H., Kovacic, L., Aviello, G., Alvarez, L. A., Griffiths, A. M., Snapper, S. B., Brant, S. R., Doroshow, J. H., Silverberg, M. S., Peter, I., Mcgovern, D. P. B., Cho, J., Brumell, J. H., Uhlig, H. H., Bourke, B., Muise, A. M., and Knaus, U. G.

Subjects
WT, wild type, NADPH Oxidase, Inflammatory bowel disease, 0302 clinical medicine, Chronic granulomatous disease, Cellular localization, Original Research, NOX1, NADPH oxidase 1, VEOIBD, very early onset inflammatory bowel disease, 0303 health sciences, NADPH oxidase, IBD, inflammatory bowel disease, HA, human influenza hemagglutinin, Gastroenterology, NADPH Oxidase 1, NADPH, nicotinamide-adenine dinucleotide phosphate, 3. Good health, medicine.anatomical_structure, NOX1, cardiovascular system, 030211 gastroenterology & hepatology, SNP, single-nucleotide polymorphism, Reactive Oxygen Specie, AJ, Ashkenazi Jewish, PMA, phorbol 12-myristate 13-acetate, PBS, phosphate-buffered saline, Biology, MAF, minor allele frequency, Microbiology, 03 medical and health sciences, PAS, periodic acid–Schiff, ROS, reactive oxygen species, medicine, lcsh:RC799-869, DUOX2, VEOIBD, 030304 developmental biology, DUOX2, dual oxidase 2, FAD, flavin adenine nucleotide, Hepatology, Inflammatory Bowel Disease, CGD, chronic granulomatous disease, Dual oxidase 2, medicine.disease, UC, ulcerative colitis, Immunology, Paneth cell, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, Reactive Oxygen Species
Abstract

Background & Aims: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD. Methods: After targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 59 children with very early onset inflammatory bowel disease (VEOIBD), the identified mutations were validated using Sanger Sequencing. A structural analysis of NOX1 and DUOX2 variants was performed by homology in silico modeling. The functional characterization included ROS generation in model cell lines and in in vivo transduced murine crypts, protein expression, intracellular localization, and cell-based infection studies with the enteric pathogens Campylobacter jejuni and enteropathogenic Escherichia coli. Results: We identified missense mutations in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn) and DUOX2 (c.4474G>A, p.Arg1211Cys; c.3631C>T, p.Arg1492Cys) in 5 of 209 VEOIBD patients. The NOX1 p.Asp360Asn variant was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. Patients with both NOX1 and DUOX2 variants showed abnormal Paneth cell metaplasia. All NOX1 and DUOX2 variants showed reduced ROS production compared with wild-type enzymes. Despite appropriate cellular localization and comparable pathogen-stimulated translocation of altered oxidases, cells harboring NOX1 or DUOX2 variants had defective host resistance to infection with C. jejuni. Conclusions: This study identifies the first inactivating missense variants in NOX1 and DUOX2 associated with VEOIBD. Defective ROS production from intestinal epithelial cells constitutes a risk factor for developing VEOIBD. Keywords: Inflammatory Bowel Disease, NADPH Oxidase, NOX1, DUOX2, Reactive Oxygen Species, VEOIBD

Published
2015
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30. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author

Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr. , W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Meyers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fisher M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann M, O'Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Mattha W, Knouf CW, Waterworth DM, Hakonarson HH, Walker M, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker B, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Uitterlinden AG, Willerson JT, van Duijn CM, Witteman JC, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Parsa A, Gao X, Yang Q, Smith AV, O'Connell JR, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson A, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria, Francesco, Metter J, de Boer J, Siscovick D, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turne ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan R, Felix SB, Watzinger N, Larson MG, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Stricker BH, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett D, Blettner M, Friedrich N, Benjamin EJ, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic T, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Abecasis GR, Lightstone L, Scott J, Navis G, Elliot P, Kooner JS., AII - Amsterdam institute for Infection and Immunity, Nephrology, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Epidemiology, Medical Microbiology & Infectious Diseases, Radiology & Nuclear Medicine, Cardiology, Internal Medicine, Clinical Genetics, Erasmus MC other, Obstetrics & Gynecology, International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Clinical Pharmacology and The Genome Centre, Queen Mary University of London (QMUL), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Center for Human Genetic Research, Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Harvard University-Massachusetts Institute of Technology (MIT), Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'An, Arora, Pankaj, Dehghan, Abba, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, Mcardle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthia, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johanne, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inê, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Marku, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margu, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Mckenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thoma, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, Jame, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr., W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Ander, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcu, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Pano, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Jano, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charle, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Mari, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang, H, Knowles, J, Hlatky, M, Fortmann, S, Assimes, Tl, Quertermous, T, Go, A, Iribarren, C, Absher, D, Risch, N, Meyers, R, Sidney, S, Ziegler, A, Schillert, A, Bickel, C, Sinning, C, Rupprecht, Hj, Lackner, K, Wild, P, Schnabel, R, Blankenberg, S, Zeller, T, Münzel, T, Perret, C, Cambien, F, Tiret, L, Nicaud, V, Proust, C, Dehghan, A, Hofman, A, Uitterlinden, A, van Duijn, C, Levy, D, Whitteman, J, Cupples, La, Demissie-Banjaw, S, Ramachandran, V, Smith, A, Gudnason, V, Boerwinkle, E, Folsom, A, Morrison, A, Psaty, Bm, Chen, Iy, Rotter, Ji, Bis, J, Volcik, K, Rice, K, Taylor, Kd, Marciante, K, Smith, N, Glazer, N, Heckbert, S, Harris, T, Lumley, T, Kong, A, Thorleifsson, G, Thorgeirsson, G, Holm, H, Gulcher, Jr, Stefansson, K, Andersen, K, Gretarsdottir, S, Thorsteinsdottir, U, Preuss, M, Schreiber, S, Meitinger, T, König, Ir, Lieb, W, Hengstenberg, C, Schunkert, H, Erdmann, J, Fisher, M, Grosshennig, A, Medack, A, Stark, K, Linsel-Nitschke, P, Bruse, P, Aherrahrou, Z, Peters, A, Loley, C, Willenborg, C, Nahrstedt, J, Freyer, J, Gulde, S, Doering, A, Meisinger, C, Wichmann, He, Klopp, N, Illig, T, Meinitzer, A, Tomaschitz, A, Halperin, E, Dobnig, H, Scharnagl, H, Kleber, M, Laaksonen, R, Pilz, S, Grammer, Tb, Stojakovic, T, Renner, W, März, W, Böhm, Bo, Winkelmann, Br, Winkler, K, Hoffmann, M, O'Donnell, Cj, Voight, Bf, Altshuler, D, Siscovick, D, Musunuru, K, Peltonen, L, Barbalic, M, Melander, O, Elosua, R, Kathiresan, S, Schwartz, Sm, Salomaa, V, Guiducci, C, Burtt, N, Gabriel, Sb, Stewart, Af, Wells, Ga, Chen, L, Jarinova, O, Roberts, R, Mcpherson, R, Dandona, S, Pichard, Ad, Rader, Dj, Devaney, J, Lindsay, Jm, Kent, Km, Qu, L, Satler, L, Burnett, M, Li, M, Reilly, Mp, Wilensky, R, Waksman, R, Epstein, S, Mattha, W, Knouf, Cw, Waterworth, Dm, Hakonarson, Hh, Walker, M, Mooser, V, Hall, A, Balmforth, Aj, Wright, Bj, Nelson, C, Thompson, Jr, Samani, Nj, Braund, P, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Rivadeneira, F, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Wang, Ya, Stricker, B, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Uitterlinden, Ag, Willerson, Jt, van Duijn, Cm, Witteman, Jc, Vasan, R, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Parsa, A, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Schmidt, H, Tanaka, T, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, A, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, Francesco, Metter, J, de Boer, J, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turne, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Larson, Mg, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Stricker, Bh, Reffelmann, T, Redfield, Mm, Werdan, K, Mitchell, Gf, Arnett, D, Blettner, M, Friedrich, N, Benjamin, Ej, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, T, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliot, P, and Kooner, Js.

Subjects
novel loci, Kidney Disease, Polymorphism, Single Nucleotide/*genetics, [SDV]Life Sciences [q-bio], left ventricular wall thickness, LOCI, Genome-wide association study, Blood Pressure, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, RELEVANCE, Africa/ethnology, Cardiovascular Disease, genetics, Kidney Diseases/genetics, Stroke, genome wide association study, POPULATION, ta118, Blood pressure, hypertension, stroke, coronary artery disease, ddc:616, 0303 health sciences, education.field_of_study, Asia/ethnology, Multidisciplinary, Coronary Artery Disease/genetics, COMMON VARIANTS, Genetic Predisposition to Disease/*genetics, 3. Good health, Europe, Cardiovascular Diseases, Hypertension, Cardiology, Kidney Diseases, HEALTH, Human, medicine.medical_specialty, Asia, Population, Renal function, Polymorphism, Single Nucleotide, Europe/ethnology, Article, CLONING, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stroke/genetics, Internal medicine, medicine, Humans, Cardiovascular Diseases/*genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, 030304 developmental biology, RECEPTOR, genes, blood pressure, cardiovascular disease risk, medicine.disease, Africa, Blood Pressure/*genetics/physiology, Hypertension/genetics, Kidney disease, Genome-Wide Association Study
Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. ispartof: Nature vol:478 issue:7367 pages:103-109 ispartof: location:England status: published

Published
2011
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31. Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up

Author

Jochen Kammermeier, Neil J. Sebire, Kanchan Rao, Neil Shah, Drew Ellershaw, Gabriele Noble-Jamieson, Marco Gasparetto, Giovanna Lucchini, Juliana Silva, Holm H. Uhlig, Robert Chiesa, Persis Amrolia, Mamoun Elawad, Austen Worth, Dyanne Rampling, Luigi D. Notarangelo, Sung-Yun Pai, and Paul Veys

Subjects
0301 basic medicine, Time Factors, Long term follow up, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, medicine.disease_cause, Bioinformatics, Biochemistry, Inflammatory bowel disease, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Gene, Mutation, business.industry, Hematopoietic Stem Cell Transplantation, Proteins, Cell Biology, Hematology, Inflammatory Bowel Diseases, medicine.disease, Transplantation, Tetratricopeptide, Treatment Outcome, 030104 developmental biology, Stem cell, business, Follow-Up Studies
Abstract

Mutations in the tetratricopeptide repeat domain 7A (TTC7A)gene cause a severe form of very early-onset inflammatory bowel disease (VEOIBD). TTC7A has a crucial role in chaperoning the enzyme phosphatidylinositol-4-Kinase-3-alpha from the Trans-Golgi apparatus to the plasma membrane to facilitate phosphorylation of phosphatidylinositol (PI). The composition of the plasma membrane in particular levels of phosphorylated PI (PI-4P) are crucial for preserving epithelial cell polarity and survival . The clinical spectrum of the disease varies from multiple intestinal atresias (MIA) to severe autoimmune enterocolitis clinically evident by infantile-onset intestinal obstruction/failure, bleeding and diarrhoea. Furthermore, the disease can be associated with severe immunodeficiency or autoimmune phenomena owing to the central role of TTC7A in thymic architecture. Limited published data on TTC7A deficient patients suggests a median survival

Published
2016
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32. Clinical genomics in inflammatory bowel disease

Author

Aleixo M. Muise and Holm H. Uhlig

Subjects
0301 basic medicine, Crohn's disease, Genome, Human, Genomics, Disease, Biology, Inflammatory Bowel Diseases, Bioinformatics, medicine.disease, Precision medicine, Inflammatory bowel disease, Ulcerative colitis, digestive system diseases, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, Genetics, medicine, Mendelian inheritance, symbols, Humans, Exome sequencing
Abstract

Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from 'orphan disease' research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD.

Published
2017
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33. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Author

Mohammed F Sadiyah, Ira Palmer, Anwar A. Sayed, Ahmad Khoder, Joshua Kaufman, Warren Strober, Alejandro V. Villarino, Paul T. Wingfield, Michael Mueller, Majid Kazemian, Joshua McElwee, Ahmed N. Hegazy, Behdad Afzali, Fred P. Davis, Julia Keith, Jason D. Hughes, Hong-Wei Sun, Charlotte O'Brien, Holm H. Uhlig, Michelle A. Linterman, Yu Zhang, Arian Laurence, Nichola Cooper, John J. O'Shea, Ine Vanderleyden, Dalia Kasperaviciute, Timothy J. Aitman, Rahul Roychoudhuri, Olena Kamenyeva, Juha Grönholm, Kim Montgomery-Recht, Ivan J. Fuss, Nicholas P. Restifo, Norman R. Watts, Peter Kelleher, Jana Vandrovcova, Michael J. Lenardo, Westminster Medical School Research Trust, Imperial College Healthcare NHS Trust- BRC Funding, Leuka, Zhang, Yu [0000-0002-6904-0372], Villarino, Alejandro V [0000-0001-8068-2176], Roychoudhuri, Rahul [0000-0002-5392-1853], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Pancytopenia, AUTOIMMUNITY, Genome-wide association study, CELL DIFFERENTIATION, Haploinsufficiency, Adrenal Cortex Hormones, Recurrence, Plasma cell differentiation, Immunology and Allergy, Respiratory Tract Infections, Immunodeficiency, Genetics, Lymphocyte differentiation, Syndrome, Middle Aged, Colitis, 3. Good health, Pedigree, TRANSCRIPTION FACTORS, Basic-Leucine Zipper Transcription Factors, PLASMA-CELL-DIFFERENTIATION, 1107 Immunology, B-CELLS, Female, FUNCTIONAL PREDICTIONS, Life Sciences & Biomedicine, Adult, Heterozygote, SUSCEPTIBILITY LOCI, SEQUENCING DATA, Fever, DATABASE, Immunology, COMMON VARIABLE IMMUNODEFICIENCY, Polymorphism, Single Nucleotide, Article, CLASSIFICATION, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Lymphopenia, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, Science & Technology, IDENTIFICATION, business.industry, Common variable immunodeficiency, Immunologic Deficiency Syndromes, medicine.disease, RISK LOCI, 030104 developmental biology, Mutation, Splenomegaly, Primary immunodeficiency, T-CELLS, business, Tomography, X-Ray Computed
Abstract

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

Published
2017
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34. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Author

Natalie J. Prescott, Holm H. Uhlig, Alison Simmons, William G. Newman, Loukas Moutsianas, David C. Wilson, Sun-Gou Ji, John C. Mansfield, Christopher J. Hawkey, Graham A. Heap, Cathryn Edwards, Charlie W. Lees, Javier Gutierrez-Achury, James Lee, Nicholas A. Kennedy, Christopher A. Lamb, Jeffrey C. Barrett, Craig Mowat, Christopher G. Mathew, Jack Satsangi, Yang Luo, Daniel L. Rice, Carl A. Anderson, Paul Henderson, Ailsa Hart, Jeremy D. Sanderson, Tariq Ahmad, Elaine R. Nimmo, Mark Tremelling, Luke Jostins, Miles Parkes, and Katrina M. de Lange

Subjects
0301 basic medicine, Integrins, Quantitative Trait Loci, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Allele, ITGB8, Gene, Alleles, Genetic association, Inflammation, Inflammatory Bowel Diseases, medicine.disease, 3. Good health, 030104 developmental biology, 030211 gastroenterology & hepatology, Genome-Wide Association Study
Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Published
2017
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35. Genetically Determined Height and Coronary Artery Disease

Author

Nelson,CP, Hamby,SE, Saleheen,D, Hopewell,JC, Zeng,L, Assimes,TL, Kanoni,S, Willenborg,C, Burgess,S, Amouyel,P, Anand,S, Blankenberg,S, Boehm,BO, Clarke,RJ, Collins,R, Dedoussis,G, Farrall,M, Franks,PW, Groop,L, Hall,AS, Hamsten,A, Hengstenberg,C, Hovingh,GK, Ingelsson,E, Kathiresan,S, Kee,F, König,IR, Kooner,J, Lehtimäki,T, März,W, McPherson,R, Metspalu,A, Nieminen,MS, O'Donnell,CJ, Palmer,CN, Peters,A, Perola,M, Reilly,MP, Ripatti,S, Roberts,R, Salomaa,V, Shah,SH, Schreiber,S, Siegbahn,A, Thorsteinsdottir,U, Veronesi,G, Wareham,N, Willer,CJ, Zalloua,PA, Erdmann,J, Deloukas,P, Watkins,H, Schunkert,H, Danesh,J, Thompson,JR, Samani,NJ, Assimes,T, Goldstein,BA, Stirrups,K, Cazier,JB, Johansson,Å, Lee,JY, Chambers,JC, Esko,T, Folkersen,L, Goel,A, Grundberg,E, Havulinna,AS, Ho,WK, Eriksson,N, Kleber,ME, Kristiansson,K, Lundmark,P, Lyytikäinen,LP, Rafelt,S, Shungin,D, Strawbridge,RJ, Thorleifsson,G, Tikkanen,E, Van, Zuydam, N, Voight,BF, Waite,LL, Zhang,W, Ziegler,A, Absher,D, Altshuler,D, Balmforth,AJ, Barroso,I, Braund,PS, Burgdorf,C, Claudi Boehm,S, Cox,D, Dimitriou,M, Do,R, Doney,AS, El, Mokhtari, Eriksson,P, Fischer,K, Fontanillas,P, Franco Cereceda,A, Gigante,B, Gustafsson,S, Hager,J, Hallmans,G, Han,BG, Hunt,SE, Kang,HM, Illig,T, Kessler,T, Knowles,JW, Kolovou,G, Kuusisto,J, Langenberg,C, Langford,C, Leander,K, Lokki,ML, Lundmark,A, McCarthy,MI, Meisinger,C, Melander,O, Mihailov,E, Maouche,S, Morris,AD, Müller Nurasyid,M, Nikus,K, Peden,JF, Rayner,NW, Rasheed,A, Rosinger,S, Rubin,D, Rumpf,MP, Schäfer,A, Sivananthan,M, Song,C, Stewart,AF, Tan,ST, Thorgeirsson,G, van, der, Schoot, CE, Wagner,PJ, Wells,GA, Wild,PS, Yang,TP, Arveiler,D, Basart,H, Boehnke,M, Boerwinkle,E, BRAMBILLA, PAOLO, Cambien,F, Cupples,AL, de, Faire, U, Dehghan,A, Diemert,P, Epstein,SE, Evans,A, Ferrario,MM, Ferrières,J, Gauguier,D, Go,AS, Goodall,AH, Gudnason,V, Hazen,SL, Holm,H, Iribarren,C, Jang,Y, Kähönen,M, Kim,HS, Klopp,N, Koenig,W, Kratzer,W, Kuulasmaa,K, Laakso,M, Laaksonen,R, Lind,L, Ouwehand,WH, Parish,S, Park,JE, Pedersen,NL, Quertermous,T, Rader,DJ, Schadt,E, Sinisalo,J, Stark,K, Stefansson,K, Trégouët,DA, Virtamo,J, Wallentin,L, Zimmermann,ME, Sandhu,MS, Pastinen,T, Syvänen,AC, Blankenberg,SS, Clarke,R, O'Donnell,C, Kooner,JS, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Other departments, Lee Kong Chian School of Medicine (LKCMedicine), Nelson, C, Hamby, S, Saleheen, D, Hopewell, J, Zeng, L, Assimes, T, Kanoni, S, Willenborg, C, Burgess, S, Amouyel, P, Anand, S, Blankenberg, S, Boehm, B, Clarke, R, Collins, R, Dedoussis, G, Farrall, M, Franks, P, Groop, L, Hall, A, Hamsten, A, Hengstenberg, C, Hovingh, G, Ingelsson, E, Kathiresan, S, Kee, F, König, I, Kooner, J, Lehtimäki, T, März, W, Mcpherson, R, Metspalu, A, Nieminen, M, O'Donnell, C, Palmer, C, Peters, A, Perola, M, Reilly, M, Ripatti, S, Roberts, R, Salomaa, V, Shah, S, Schreiber, S, Siegbahn, A, Thorsteinsdottir, U, Veronesi, G, Wareham, N, Willer, C, Zalloua, P, Erdmann, J, Deloukas, P, Watkins, H, Schunkert, H, Danesh, J, Thompson, J, Samani, N, Goldstein, B, Stirrups, K, Cazier, J, Johansson, Å, Lee, J, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van, Z, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El, M, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van, D, Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De, F, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Quertermous, T, Rader, D, Schadt, E, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Zimmermann, M, Sandhu, M, Pastinen, T, Syvänen, A, Burgess, Stephen [0000-0001-5365-8760], Wareham, Nicholas [0000-0003-1422-2993], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
systolic blood pressure, Pathology, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, genetic association, genotype, cholesterol blood level, insulin blood level, Coronary Artery Disease, 030204 cardiovascular system & hematology, genetic risk, Triglyceride, low density lipoprotein cholesterol, Coronary artery disease, 0302 clinical medicine, high density lipoprotein cholesterol, single nucleotide polymorphism, Risk Factors, genetic variability, Odds Ratio, hyperlipidemia, Science::Medicine [DRNTU], genetics, glucose, risk, 0303 health sciences, medicine.diagnostic_test, non insulin dependent diabetes mellitus, Medicine (all), allele, insulin, triacylglycerol, triacylglycerol, adult, aged, Article, atherosclerosis, bioinformatics, body height, body mass, cardiovascular risk, controlled study, coronary artery disease, development, diastolic blood pressure, female, glucose blood level, human, major clinical study, male, mean arterial pressure, priority journal, pulse pressure, risk factor, smoking, triacylglycerol blood level, blood, complication, risk, Adult, Body Height, Cholesterol, LDL, Genetic Variation, Humans, Hyperlipidemias, Triglycerides, General Medicine, Cholesterol, Cardiology, Adult, medicine.medical_specialty, Inverse Association, Single-nucleotide polymorphism, Endocrinology and Diabetes, LDL, 03 medical and health sciences, Internal medicine, medicine, Risk factor, 030304 developmental biology, Genetic association, business.industry, Odds ratio, medicine.disease, Lipid profile, business, Body mass index
Abstract

BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P

Published
2015

36. Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies

Author

Andreas Laner, Frank Kowalzik, Adrian Viehweger, Franziska Wilhelm, Susanne Schuster, Gordian L. Schmid, Norman Händel, Wieland Kiess, Fred-P. Zepp, Wolfgang Hirsch, Jürgen Kratzsch, Franziska Kässner, Antje Körner, Sven Starke, Holm H. Uhlig, and Antje Garten

Subjects
Lipomatosis, In Vitro Techniques, Drug therapy, Hamartoma, Paediatrics, PTEN, PHTS, PI3K, AKT, mTOR, medicine, Humans, Tensin, PTEN, ddc:610, Protein kinase B, PI3K/AKT/mTOR pathway, Sirolimus, biology, business.industry, Infant, Newborn, PTEN Phosphohydrolase, Infant, Lipoma, medicine.disease, Child, Preschool, Pediatrics, Perinatology and Child Health, Cancer research, biology.protein, Thymus hyperplasia, Hamartoma Syndrome, Multiple, business, medicine.drug
Abstract

Background: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is caused by germ line mutations in the PTEN gene. Symptoms include cancer pre- disposition, immune deviations, and lipomas/lipomatosis. No causal standard therapy is available. We describe a therapeutic attempt with the mammalian target of rapamycin (mTOR) inhibitor sirolimus for a PHTS patient suffering from thymus hyperplasia and lipomatosis. We furthermore assessed the in vitro effects of sirolimus and other inhibitors on lipoma cells of the patient. Methods: The patient underwent clinical and blood examinations and whole-body magnetic resonance imaging to assess tumor sizes. Lipoma cells of the patient were incubated with inhibitors of the phosphoinositide3-kinase (PI3K)/AKT/ mTOR signaling pathway to analyze the effects on proliferation, adipocyte differentiation, and survival in vitro. Results: Sirolimus treatment improved somatic growth and reduced thymus volume. These effects diminished over the treatment period of 19 mo. Sirolimus decreased lipoma cell proliferation and adipocyte differentiation in vitro but did not cause apoptosis. PI3K and AKT inhibitors induced apoptosis significantly. Conclusion: Sirolimus treatment led to an improvement of the patient’s clinical status and a transient reduction of the thymus. Our in vitro findings point to PI3K and AKT inhibitors as potential treatment options for patients with severe forms of PHTS.

Published
2013
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37. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

Author

Holm H. Uhlig

Subjects
Adult, Adolescent, Regulatory T cell, Disease, Biology, Lymphocyte Activation, T-Lymphocytes, Regulatory, Inflammatory bowel disease, Young Adult, Crohn Disease, Intestinal mucosa, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Intestinal Mucosa, Child, Immunodeficiency, Aged, Aged, 80 and over, Inflammation, Crohn's disease, Gastroenterology, Infant, Middle Aged, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, digestive system diseases, Transplantation, medicine.anatomical_structure, Child, Preschool, Immunology, Colitis, Ulcerative
Abstract

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.

Published
2013
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38. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author

Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, AAI12, Chemistry(all), SUSCEPTIBILITY LOCI, Science, Population, General Physics and Astronomy, Physics and Astronomy(all), OF-FUNCTION VARIANTS, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, NUMBER, medicine, Ring finger, IMPUTATION, Allele, education, POPULATION, RISK, education.field_of_study, Multidisciplinary, biology, Biochemistry, Genetics and Molecular Biology(all), MUTATIONS, General Chemistry, ASSOCIATION, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Ubiquitin ligase, Transport protein, Transmembrane domain, 030104 developmental biology, medicine.anatomical_structure, RARE VARIANTS, Immunology, biology.protein, Cancer research, 3111 Biomedicine, INFLAMMATORY-BOWEL-DISEASE
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763

Published
2016
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39. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells

Author

Simon Read, Magda Strus, Tomas Hrncir, Olga Kofronova, Tomas Hudcovic, Paul W. Bland, Helena Tlaskalova-Hogenova, Fiona Powrie, Pioter Heczko, Oldrich Benada, Holm H. Uhlig, Z Reháková, Hana Kozakova, and Renata Stepankova

Subjects
CD4-Positive T-Lymphocytes, Adoptive cell transfer, Segmented filamentous bacteria, Spleen, Mice, SCID, Biology, Inflammatory bowel disease, Microbiology, Mice, Fusobacterium mortiferum, Intestinal mucosa, medicine, Immunology and Allergy, Animals, Colitis, Intestinal Mucosa, In Situ Hybridization, Fluorescence, Severe combined immunodeficiency, Mice, Inbred BALB C, Hyperplasia, Gastroenterology, Hypertrophy, medicine.disease, Flow Cytometry, Adoptive Transfer, Disease Models, Animal, medicine.anatomical_structure, Microscopy, Electron, Scanning, Leukocyte Common Antigens
Abstract

Background: The aim was to analyze the influence of intestinal microbiota on the development of intestinal inflammation. We used the model of chronic inflammation that develops spontaneously in the colon of conventional severe combined immunodeficiency (SCID) mice restored with the CD45 RBhigh subset of CD4+T cells isolated from the spleen of normal BALB/c mice. Methods: A CD4+CD45RBhigh subpopulation of T cells was purified from the spleen of conventional BALB/c mice by magnetic separation (MACS) and transferred into immunodeficient SCID mice. Germ-free (GF) SCID mice or SCID mice monoassociated with Enterococcus faecalis, SFB (segmented filamentous bacteria), Fusobacterium mortiferum, Bacteroides distasonis, and in combination Fusobacterium mortiferum + SFB or Bacteroides distasonis + SFB were used as recipients. SCID mice were colonized by a defined cocktail of specific pathogen-free (SPF) bacteria. Mice were evaluated 8–12 weeks after the cell transfer for clinical and morphological signs of inflammatory bowel disease (IBD). Results: After the transfer of the CD4+CD45RBhigh T-cell subpopulation to SCID mice severe colitis was present in conventional animals and in mice colonized with a cocktail of SPF microflora plus SFB. Altered intestinal barrier in the terminal ileum of mice with severe colitis was documented by immunohistology using antibodies to ZO-1 (zona occludens). Conclusions: Only SFB bacteria together with a defined SPF mixture were effective in triggering intestinal inflammation in the model of IBD in reconstituted SCID mice, while no colitis was detected in GF mice or in mice colonized either with SPF microflora or monoassociated only with SFB or colonized by Bacteroides distasonis + SFB or Fusobacterium mortiferum + SFB. (Inflamm Bowel Dis 2007)

Published
2016

40. IgG antibodies against deamidated gliadin peptides for diagnosis of celiac disease in patients with IgA deficiency

Author

Martin W. Laass, Thomas Richter, Xavier Bossuyt, Christian Prause, Sibylle Koletzko, Martin Stern, Wolfgang Schlumberger, Julia H. Ellis, Pieter Vermeersch, Danilo Villalta, Paul J. Ciclitira, Thomas Mothes, Elio Tonutti, Cornelia Daehnrich, and Holm H. Uhlig

Subjects
Adult, Male, Adolescent, Tissue transglutaminase, Clinical Biochemistry, Immunofluorescence, Sensitivity and Specificity, Coeliac disease, Immunoglobulin G, Gliadin, Immunopathology, medicine, Humans, Child, Aged, biology, medicine.diagnostic_test, business.industry, Biochemistry (medical), IgA Deficiency, Middle Aged, medicine.disease, Endomysium, Celiac Disease, medicine.anatomical_structure, Child, Preschool, Immunology, biology.protein, Female, Antibody, business, Peptides
Abstract

Background: Assays for IgG antibodies against deamidated gliadin (IgG-anti-dGli) are comparable in performance with tests detecting IgA antibodies against tissue transglutaminase (IgA-anti-tTG) in diagnosing celiac disease (CD). IgA-anti-tTG are absent in IgA deficiency, a condition often associated with CD. In IgA deficiency, IgG-anti-tTG, which have a lower overall diagnostic accuracy, are routinely measured. We examined whether IgG-anti-dGli would be useful for diagnosing CD in patients with IgA deficiency.Methods: We studied 34 IgA-deficient CD patients, 185 IgA-competent newly diagnosed children with CD, 316 children without CD, 400 adult blood donors, and 6 control IgA-deficient individuals without CD. Anti-dGli and anti-tTG were measured by ELISA, and endomysium antibodies (EmA) were measured by immunofluorescence on monkey esophagus (IgA as well as IgG class for all antibodies). We calculated diagnostic sensitivity (percentage of patients above cutoff with 95% CIs) according to age-specific cutoffs for 95% diagnostic specificity and according to cutoffs proposed by the manufacturer of the assays.Results: No IgA-deficient CD patients were positive for any IgA-based antibody assay. Diagnostic sensitivity of IgG-anti-tTG was 91.2% (95% CI 76.3%–97.7%) according to age-specific cutoffs and 82.4% (66.1%–92.0%) according to manufacturer cutoffs. The diagnostic sensitivity of IgG-EmA was 75.8% (58.8%–87.4%) and the sensitivity of IgG-anti-dGli was 88.2% (72.8%–95.9%) according to both cutoffs.Conclusions: IgG-anti-dGli and IgG-anti-tTG have comparable diagnostic sensitivities for IgA-deficient celiac patients. IgG-anti-dGli may be useful for diagnosing CD in IgA-deficient patients.

Published
2016
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41. Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease

Author

Fiona Powrie and Holm H. Uhlig

Subjects
Immunology, Inflammation, Biology, Mouse model of colorectal and intestinal cancer, Models, Biological, T-Lymphocytes, Regulatory, Inflammatory bowel disease, Pathogenesis, Mice, Transforming Growth Factor beta, medicine, Animals, Humans, Immunology and Allergy, Colitis, Crohn's disease, Bacteria, Autophagy, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, Gastroenteritis, Interleukin-10, Intestines, Disease Models, Animal, Host-Pathogen Interactions, medicine.symptom, Signal Transduction
Abstract

Mouse models of intestinal inflammation resemble aspects of inflammatory bowel disease in humans. These models have provided important insights into mechanisms that control intestinal homeostasis and regulation of intestinal inflammation. This viewpoint discusses themes that have emerged from mouse models of intestinal inflammation including bacterial recognition, autophagy, the IL-23/Th-17 axis of inflammation as well as the role of negative regulators. Many of the pathways highlighted by model systems have been identified in recent genome-wide association studies in human validating the relevance of mouse models to human inflammatory bowel disease. Understanding of the complex biological mechanisms that lead to intestinal inflammation in mouse models may help to define targets for treatment of human diseases.

Published
2016
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42. Variants in TRIM22 that affect NOD2 signaling are associated with very early onset inflammatory bowel disease

Author

Carrie Brodmerkel, Dror S. Shouval, Cheng Hiang Lee, Brian A. Kidd, Yongzhong Zhao, Mark Curran, Ke Hao, Ernest Cutz, Anne M. Griffiths, Holm H. Uhlig, Brigitte Snanter-Nanan, Qi Li, Colette Deslandres, Daniel Kotlarz, Scott B. Snapper, Antonio Di’Narzo, Radu Dobrin, Ziad Al Adham, Tobias Schwerd, Cornelia Thoeni, Elie Haddad, Mingjing Hu, Abdul Elkadri, Melanie Wong, Lucas A. Mastropaolo, Chaim M. Roifman, Aleixo M. Muise, Kevin J. Gaskin, Lauren A. Peters, John H. Brumell, Gabriel E. Hoffman, Christoph Klein, Ryan Murchie, Bin Zhang, Ralph Nanan, Eric E. Schadt, Thomas D. Walters, Conghui Guo, Jun Zhu, and Françoise Le Deist

Subjects
0301 basic medicine, Nod2 Signaling Adaptor Protein, Genome-wide association study, Disease, Bioinformatics, Severity of Illness Index, Inflammatory bowel disease, Tripartite Motif Proteins, Consanguinity, Crohn Disease, Germany, NOD2, Databases, Genetic, Exome, Gene Regulatory Networks, Protein Interaction Maps, NF-kB, Age of Onset, Cells, Cultured, Exome sequencing, Ontario, Homozygote, Gastroenterology, Pedigree, 3. Good health, Phenotype, England, Female, Signal Transduction, Biology, Transfection, Article, Minor Histocompatibility Antigens, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, VEOIBD, Genetic Association Studies, Hepatology, Gene Expression Profiling, Australia, Infant, Newborn, Computational Biology, Genetic Variation, Antiviral and Antibacterial Networks, medicine.disease, digestive system diseases, Repressor Proteins, 030104 developmental biology, Immunology, Calprotectin, Age of onset
Abstract

Background & Aims Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. Methods We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. Results We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)−dependent activation of interferon-beta signaling and nuclear factor−κB. Computational studies demonstrated a correlation between the TRIM22−NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. Conclusions In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Published
2016

43. Angiodysplasia as a cause of gastrointestinal bleeding in childhood

Author

Wieland Kiess, Holm H. Uhlig, J Deutscher, S Stephan, and T Richter

Subjects
Gastrointestinal bleeding, medicine.medical_specialty, Biopsy, Remission, Spontaneous, Proctoscopy, Gastroenterology, Angiodysplasia, Lesion, Recurrence, Internal medicine, medicine, Humans, Intestinal Mucosa, Child, Pathological, medicine.diagnostic_test, business.industry, Rectum, medicine.disease, Endoscopy, Pediatrics, Perinatology and Child Health, Vascular Disorder, Female, medicine.symptom, Gastrointestinal Hemorrhage, business, Follow-Up Studies
Abstract

UNLABELLED: Whereas in adults angiodysplasia is a frequent cause of gastrointestinal bleeding, in children this disorder is extremely rare. A 7 10/12 year old girl is presented suffering over 3-4 months from mild but recurrent rectal bleeding. Blood count and serum ferritin and transferrin levels were normal. The rectosigmoideoscopy revealed a rectal lesion, which was confirmed histologically as angiodysplasia. Pathological investigation of the biopsies included HE staining and immunohistological staining of endothelial cells with anti-CD34 and anti-von Willebrand factor. A follow-up period of three years revealed spontaneous regression of the angiodysplastic lesion at the rectosigmoideal localisation, which could be confirmed by endoscopy. CONCLUSION: The outcome of the few pediatric patients described in the literature was reviewed. Due to the lack of conclusive understanding of the nature of this extremely rare vascular disorder and the variable outcome described, a wait and see attitude should be assumed in cases of less clinical affection.

Published
2016
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44. From genes to mechanisms: the expanding spectrum of monogenic disorders associated with inflammatory bowel disease

Author

Tobias Schwerd and Holm H. Uhlig

Subjects
0301 basic medicine, Genetics, Crohn's disease, Gastroenterology, Genetic Diseases, Inborn, Context (language use), Genome-wide association study, Biology, medicine.disease, Inflammatory Bowel Diseases, Penetrance, Inflammatory bowel disease, digestive system, digestive system diseases, 03 medical and health sciences, 030104 developmental biology, Genes, NOD2, medicine, Genetic predisposition, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Exome sequencing
Abstract

Inborn errors of the intestinal epithelial barrier function as well as the innate and adaptive mucosal immune responses toward the intestinal microbiota are a group of genetic disorders that confer susceptibility to monogenic and syndromal forms of inflammatory bowel disease (IBD). There is a continuous spectrum of genetic susceptibility from monogenic causative variants with complete Mendelian inheritance, over NOD2 variants with moderate penetrance to minute penetrance in most common susceptibility variants predisposing to conventional polygenic IBD. We discuss advances to understand monogenic IBD and review recently identified genetic defects. We describe an integrative model for genetic susceptibility variants of conventional IBD and monogenic IBD-like intestinal inflammation in the context of microbial commensal colonization and infection susceptibility.

Published
2016
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45. The role of mucosal T lymphocytes in regulating intestinal inflammation

Author

Fiona Powrie and Holm H. Uhlig

Subjects
Innate immune system, Regulatory T cell, Immunology, Innate lymphoid cell, General Medicine, T lymphocyte, Biology, medicine.disease, Colitis, Inflammatory Bowel Diseases, Inflammatory bowel disease, T-Lymphocytes, Regulatory, TCIRG1, Intestines, medicine.anatomical_structure, Intestinal mucosa, T-Lymphocyte Subsets, medicine, Animals, Cytokines, Humans, IL-2 receptor, Intestinal Mucosa
Abstract

Suppression of chronic intestinal inflammation by different subtypes of T cells has been described in recent years. In particular, naturally arising CD4(+)CD25(+) regulatory T cells and IL-10-producing regulatory T cell type 1 CD4(+) T lymphocytes have been implicated in the regulation of intestinal inflammation. Here we focus on the ability of CD4(+)CD25(+) regulatory T cells to suppress innate and T-cell responses and discuss implications for immunoregulation in human inflammatory bowel disease. Besides the modulation of lymphoproliferation, a role for CD4(+)CD25(+) T cells in down-modulation of innate immune responses is emerging and the immunoregulatory activities of regulatory T cells in vivo may be mediated via effects on dendritic cells. Considering the extraordinary regenerative potential of the intestinal mucosa, the ability to impede pathogenic T-cell responses by active regulation might be of particular therapeutic benefit for the treatment of chronic intestinal inflammatory diseases such as Crohn's disease and ulcerative colitis.

Published
2016
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46. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Author

Graham A. Heap, James Lee, Nicholas A. Kennedy, Cathryn Edwards, Ailsa Hart, Daniel L. Rice, Javier Gutierrez-Achury, Christopher J. Hawkey, Jeremy D. Sanderson, Luke Jostins, Miles Parkes, Katrina M. de Lange, Mark Tremelling, David C. Wilson, Jeffrey C. Barrett, Carl A. Anderson, William G. Newman, Sun-Gou Ji, Elaine R. Nimmo, Paul Henderson, Natalie J. Prescott, Jack Satsangi, Christopher G. Mathew, Loukas Moutsianas, Yang Luo, Charlie W. Lees, Alison Simmons, Tariq Ahmad, Holm H. Uhlig, John C. Mansfield, Craig Mowat, and Christopher A. Lamb

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Disease, Biology, medicine.disease, Inflammatory bowel disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, 030220 oncology & carcinogenesis, medicine, Allele, ITGB8, Gene, 030304 developmental biology, Genetic association
Abstract

Genetic association studies have identified 210 risk loci for inflammatory bowel disease1–7, which have revealed fundamental aspects of the molecular biology of the disease, including the roles of autophagy and Th17 cell signaling and development. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 26 new genome-wide significant loci, three of which contain integrin genes that encode molecules in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are also correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at two previously implicated integrin loci (ITGAL, ICAM1). In all four cases, the stimulus-dependent expression increasing allele also increases disease risk. We applied summary statistic fine-mapping and identified likely causal missense variants in the primary immune deficiency genePLCG2and the negative regulator of inflammation,SLAMF8. Our results demonstrate that new common variant associations continue to identify genes and pathways of relevance to therapeutic target identification and prioritization.

Published
2016
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47. ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation

Author

Fiona Powrie, Thibault Griseri, Holm H. Uhlig, Sim Tung, Claire Pearson, Emily E. Thornton, Nathaniel Richard West, Anna-Lena Schaupp, Nicky Huskens, Benedict Seddon, and Brent S. McKenzie

Subjects
0301 basic medicine, Mouse, QH301-705.5, colitis, Science, Immunology, Population, innate lymphoid cells, Granulocyte, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, mucosal immunology, Immunity, medicine, Humans, Lymphocytes, Biology (General), Colitis, skin and connective tissue diseases, education, education.field_of_study, General Immunology and Microbiology, Effector, General Neuroscience, Innate lymphoid cell, Granulocyte-Macrophage Colony-Stimulating Factor, live imaging, General Medicine, medicine.disease, Immunity, Innate, 3. Good health, Intestines, 030104 developmental biology, medicine.anatomical_structure, Granulocyte macrophage colony-stimulating factor, Mucosal immunology, 030220 oncology & carcinogenesis, innate lymphoid cell, Interleukin-23 Subunit p19, Medicine, Research Article, Human, medicine.drug
Abstract

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response. DOI: http://dx.doi.org/10.7554/eLife.10066.001, eLife digest Crohn’s disease and ulcerative colitis are diseases in which the body’s own immune system causes inflammation of the large intestine. These autoimmune diseases can be severely debilitating and difficult to treat. However an improved understanding of the factors that contribute to the intestinal inflammation may lead to new and effective treatments. Immune cells called innate lymphoid cells were discovered recently, and shown quickly to play a role in host defense, tissue repair and inflammation regulation. Several groups of innate lymphoid cells are now known; each group is characterized by the genes that control the cell’s development and the small proteins (called cytokines) that the cells release. One group of innate lymphoid cells, the ILC3s, are generally found in the intestinal tract, albeit in small numbers. Given that innate lymphoid cells are known to manage inflammatory responses, it is possible that ILC3s contribute to intestinal inflammation. However, it remains unclear how such a small population of cells could so dramatically inflame the gut. Pearson et al. now reveal two mechanisms that these innate lymphoid cells use to amplify the inflammatory response and exacerbate intestinal inflammation. First, in both mice and humans, ILC3s were found to be a key source of a cytokine called GM-CSF, which recruits additional immune cells that further promote intestinal inflammation. Secondly, while ILC3s were traditionally regarded as immobile immune cells, Pearson et al. discovered that these cells can move within the intestinal tissue and mobilize from their starting points within this tissue if they are activated. These two mechanisms could explain how ILC3s can trigger inflammation that occurs throughout the gut. The experiments suggest that blocking production of the GM-CSF cytokine or altering ILC3 movement or activity may help reduce intestinal inflammation. However, the use of GM-CSF blocking drugs to protect against colitis and similar conditions could be problematic, because GM-CSF also plays an important protective role in the intestines. Nevertheless, clinical trials are underway to investigate the use of anti-GM-CSF drugs to treat other inflammatory conditions (such as rheumatoid arthritis). These studies could offer insight into whether these drugs provide relief to trial participants who suffer from intestinal inflammation as well. DOI: http://dx.doi.org/10.7554/eLife.10066.002

Published
2016
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48. NOD2 mutations predict the risk for surgery in pediatric-onset Crohn's disease

Author

Roland Kappler, Sebastian Schroepf, Peter Lohse, Johanna Helmbrecht, Antje Ballauff, Dominik Hartl, Jochen Hubertus, Martin Lacher, Dietrich von Schweinitz, Martin Classen, Sibylle Koletzko, and Holm H. Uhlig

Subjects
Male, Heterozygote, medicine.medical_specialty, Adolescent, Genotype, Nod2 Signaling Adaptor Protein, Medizin, Disease, medicine.disease_cause, Inflammatory bowel disease, Crohn Disease, Risk Factors, NOD2, Humans, Medicine, Genetic Predisposition to Disease, Age of Onset, Child, Genetic testing, Mutation, medicine.diagnostic_test, Ileal Diseases, business.industry, Intracellular Signaling Peptides and Proteins, General Medicine, medicine.disease, digestive system diseases, Surgery, Phenotype, Pediatrics, Perinatology and Child Health, Cohort, Female, Age of onset, business
Abstract

BACKGROUND/PURPOSE: Three common mutations of the NOD2/CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood-onset CD patients. METHODS: Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease

Published
2010
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49. Su1795 - Developing an Index that Predicts Escalation of Therapy at an Outpatient Appointment in Patients with Known Ulcerative Colitis (UC)

Author

Satish Keshav, Alissa Walsh, Gary S. Collins, Holm H. Uhlig, Guy M. Goodwin, Vanashree Sexton, Simon Travis, Chris Hinds, John R. Geddes, Jean M. Wilson, and Oliver Brain

Subjects
medicine.medical_specialty, Index (economics), Hepatology, business.industry, Internal medicine, Gastroenterology, Medicine, In patient, business, medicine.disease, Ulcerative colitis
Published
2018
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50. P037 Bacterial handling defect in macrophages of patients with defects in glucose-6-phosphate metabolism and Crohn’s disease like intestinal inflammation

Author

Holm H. Uhlig, D Aschenbrenner, K Balagopal, Britta Siegmund, Sumeet Pandey, Carl Weidinger, J McCullagh, E Pires, Melania Capitani, Simon Travis, and J F Ziegler

Subjects
Crohn's disease, Glucose 6-phosphate metabolism, business.industry, Intestinal inflammation, Immunology, Gastroenterology, Medicine, General Medicine, business, medicine.disease
Published
2018
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