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19 results on '"Halfvarson, Jonas"'

1. Dynamics of the human gut microbiome in inflammatory bowel disease.

Author

Halfvarson, Jonas, Brislawn, Colin J, Lamendella, Regina, Vázquez-Baeza, Yoshiki, Walters, William A, Bramer, Lisa M, D'Amato, Mauro, Bonfiglio, Ferdinando, McDonald, Daniel, Gonzalez, Antonio, McClure, Erin E, Dunklebarger, Mitchell F, Knight, Rob, and Jansson, Janet K

Subjects
Feces, Humans, Colitis, Ulcerative, Inflammatory Bowel Diseases, Crohn Disease, Inflammation, Leukocyte L1 Antigen Complex, Cross-Sectional Studies, Phenotype, Adult, Female, Male, Dysbiosis, Gastrointestinal Microbiome, Microbiology, Medical Microbiology
Abstract

Inflammatory bowel disease (IBD) is characterized by flares of inflammation with a periodic need for increased medication and sometimes even surgery. The aetiology of IBD is partly attributed to a deregulated immune response to gut microbiome dysbiosis. Cross-sectional studies have revealed microbial signatures for different IBD subtypes, including ulcerative colitis, colonic Crohn's disease and ileal Crohn's disease. Although IBD is dynamic, microbiome studies have primarily focused on single time points or a few individuals. Here, we dissect the long-term dynamic behaviour of the gut microbiome in IBD and differentiate this from normal variation. Microbiomes of IBD subjects fluctuate more than those of healthy individuals, based on deviation from a newly defined healthy plane (HP). Ileal Crohn's disease subjects deviated most from the HP, especially subjects with surgical resection. Intriguingly, the microbiomes of some IBD subjects periodically visited the HP then deviated away from it. Inflammation was not directly correlated with distance to the healthy plane, but there was some correlation between observed dramatic fluctuations in the gut microbiome and intensified medication due to a flare of the disease. These results will help guide therapies that will redirect the gut microbiome towards a healthy state and maintain remission in IBD.

Published
2017

2. A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn’s Disease and Human Gut Microbiome Composition

Author

Li, Dalin, Achkar, Jean-Paul, Haritunians, Talin, Jacobs, Jonathan P, Hui, Ken Y, D'Amato, Mauro, Brand, Stephan, Radford-Smith, Graham, Halfvarson, Jonas, Niess, Jan-Hendrik, Kugathasan, Subra, Büning, Carsten, Schumm, L Philip, Klei, Lambertus, Ananthakrishnan, Ashwin, Aumais, Guy, Baidoo, Leonard, Dubinsky, Marla, Fiocchi, Claudio, Glas, Jürgen, Milgrom, Raquel, Proctor, Deborah D, Regueiro, Miguel, Simms, Lisa A, Stempak, Joanne M, Targan, Stephan R, Törkvist, Leif, Sharma, Yashoda, Devlin, Bernie, Borneman, James, Hakonarson, Hakon, Xavier, Ramnik J, Daly, Mark, Brant, Steven R, Rioux, John D, Silverberg, Mark S, Cho, Judy H, Braun, Jonathan, McGovern, Dermot PB, and Duerr, Richard H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Genetics, Nutrition, Inflammatory Bowel Disease, Autoimmune Disease, Human Genome, Clinical Research, Digestive Diseases, Crohn's Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Alleles, Case-Control Studies, Cation Transport Proteins, Colitis, Ulcerative, Crohn Disease, Female, Gastrointestinal Microbiome, Genetic Pleiotropy, Genotype, Humans, Male, Mutation, Missense, Risk Factors, Inflammatory Bowel Diseases, Microbiota, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsGenome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).MethodsGenotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.ResultsWe identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).ConclusionsOur results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Published
2016

3. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

Author

Rivas, Manuel, Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, A, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Sören, Kurki, Mitja, Li, Dalin, DAmato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse, Halfvarson, Jonas, Paavola-Sakki, Paulina, Lappalainen, Maarit, Lek, Monkol, Cummings, Beryl, Tukiainen, Taru, Haritunians, Talin, Halme, Leena, Koskinen, Lotta, Ananthakrishnan, Ashwin, Luo, Yang, Heap, Graham, Visschedijk, Marijn, MacArthur, Daniel, Neale, Benjamin, Ahmad, Tariq, Anderson, Carl, Brant, Steven, Duerr, Richard, Silverberg, Mark, Cho, Judy, Palotie, Aarno, Saavalainen, Päivi, Kontula, Kimmo, Färkkilä, Martti, McGovern, Dermot, Franke, Andre, Stefansson, Kari, Rioux, John, Xavier, Ramnik, Daly, Mark, Barrett, J, de Lane, K, Edwards, C, Hart, A, Hawkey, C, Jostins, L, Kennedy, N, Lamb, C, Lee, J, Lees, C, Mansfield, J, Mathew, C, Mowatt, C, Newman, B, Nimmo, E, Parkes, M, Pollard, M, Prescott, N, Randall, J, Rice, D, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, D, Abraham, C, Achkar, J, Bitton, A, Boucher, G, Croitoru, K, Fleshner, P, Glas, J, Kugathasan, S, Limbergen, J, Milgrom, R, Proctor, D, Regueiro, M, Schumm, P, Sharma, Y, Stempak, J, Targan, S, and Wang, M

Subjects
Alleles, Colitis, Ulcerative, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Mutation, Protein Transport, RNA, Messenger, Reproducibility of Results, Sequence Analysis, DNA, Ubiquitin-Protein Ligases
Abstract

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.

Published
2016

4. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Author

Ellinghaus, David, Jostins, Luke, Spain, Sarah L, Cortes, Adrian, Bethune, Jörn, Han, Buhm, Park, Yu Rang, Raychaudhuri, Soumya, Pouget, Jennie G, Hübenthal, Matthias, Folseraas, Trine, Wang, Yunpeng, Esko, Tonu, Metspalu, Andres, Westra, Harm-Jan, Franke, Lude, Pers, Tune H, Weersma, Rinse K, Collij, Valerie, D'Amato, Mauro, Halfvarson, Jonas, Jensen, Anders Boeck, Lieb, Wolfgang, Degenhardt, Franziska, Forstner, Andreas J, Hofmann, Andrea, Schreiber, Stefan, Mrowietz, Ulrich, Juran, Brian D, Lazaridis, Konstantinos N, Brunak, Søren, Dale, Anders M, Trembath, Richard C, Weidinger, Stephan, Weichenthal, Michael, Ellinghaus, Eva, Elder, James T, Barker, Jonathan NWN, Andreassen, Ole A, McGovern, Dermot P, Karlsen, Tom H, Barrett, Jeffrey C, Parkes, Miles, Brown, Matthew A, and Franke, Andre

Subjects
Biological Sciences, Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Bayes Theorem, Cholangitis, Sclerosing, Chronic Disease, Colitis, Ulcerative, Comorbidity, Crohn Disease, Genetic Heterogeneity, Genetic Pleiotropy, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Inflammation, Psoriasis, Quantitative Trait Loci, Spondylitis, Ankylosing, International IBD Genetics Consortium, International Genetics of Ankylosing Spondylitis Consortium, International PSC Study Group, Genetic Analysis of Psoriasis Consortium, Psoriasis Association Genetics Extension, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

Published
2016

5. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

Author

Ellinghaus, David, Zhang, Hu, Zeissig, Sebastian, Lipinski, Simone, Till, Andreas, Jiang, Tao, Stade, Björn, Bromberg, Yana, Ellinghaus, Eva, Keller, Andreas, Rivas, Manuel A, Skieceviciene, Jurgita, Doncheva, Nadezhda T, Liu, Xiao, Liu, Qing, Jiang, Fuman, Forster, Michael, Mayr, Gabriele, Albrecht, Mario, Häsler, Robert, Boehm, Bernhard O, Goodall, Jane, Berzuini, Carlo R, Lee, James, Andersen, Vibeke, Vogel, Ulla, Kupcinskas, Limas, Kayser, Manfred, Krawczak, Michael, Nikolaus, Susanna, Weersma, Rinse K, Ponsioen, Cyriel Y, Sans, Miquel, Wijmenga, Cisca, Strachan, David P, McArdle, Wendy L, Vermeire, Séverine, Rutgeerts, Paul, Sanderson, Jeremy D, Mathew, Christopher G, Vatn, Morten H, Wang, Jun, Nöthen, Markus M, Duerr, Richard H, Büning, Carsten, Brand, Stephan, Glas, Jürgen, Winkelmann, Juliane, Illig, Thomas, Latiano, Anna, Annese, Vito, Halfvarson, Jonas, D'Amato, Mauro, Daly, Mark J, Nothnagel, Michael, Karlsen, Tom H, Subramani, Suresh, Rosenstiel, Philip, Schreiber, Stefan, Parkes, Miles, and Franke, Andre

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Biotechnology, Genetics, Inflammatory Bowel Disease, Autoimmune Disease, Human Genome, Clinical Research, Digestive Diseases, Crohn's Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Inflammatory and immune system, Adolescent, Adult, Case-Control Studies, Colitis, Ulcerative, Crohn Disease, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mutation, Missense, Nuclear Proteins, Polymorphism, Single Nucleotide, Positive Regulatory Domain I-Binding Factor 1, Quantitative Trait Loci, Repressor Proteins, Young Adult, Whole-Exome Sequencing, Complex Disease, CD, Crohn’s disease, GWAS, IBD, IFN, NF-κB, PBL, PBMC, SNP, SNV, TLR, Toll-like receptor, UC, WT, eQTL, expression quantitative trait locus, genome-wide association studies, inflammatory bowel disease, interferon, nuclear factor κB, peripheral blood lymphocyte, peripheral blood mononuclear cell, qRT-PCR, quantitative reverse-transcription polymerase chain reaction, single nucleotide polymorphism, single nucleotide variant, ulcerative colitis, wild-type, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Published
2013

6. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author

Anderson, Carl A, Boucher, Gabrielle, Lees, Charlie W, Franke, Andre, D'Amato, Mauro, Taylor, Kent D, Lee, James C, Goyette, Philippe, Imielinski, Marcin, Latiano, Anna, Lagacé, Caroline, Scott, Regan, Amininejad, Leila, Bumpstead, Suzannah, Baidoo, Leonard, Baldassano, Robert N, Barclay, Murray, Bayless, Theodore M, Brand, Stephan, Büning, Carsten, Colombel, Jean-Frédéric, Denson, Lee A, De Vos, Martine, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Fehrmann, Rudolf SN, Floyd, James AB, Florin, Timothy, Franchimont, Denis, Franke, Lude, Georges, Michel, Glas, Jürgen, Glazer, Nicole L, Guthery, Stephen L, Haritunians, Talin, Hayward, Nicholas K, Hugot, Jean-Pierre, Jobin, Gilles, Laukens, Debby, Lawrance, Ian, Lémann, Marc, Levine, Arie, Libioulle, Cecile, Louis, Edouard, McGovern, Dermot P, Milla, Monica, Montgomery, Grant W, Morley, Katherine I, Mowat, Craig, Ng, Aylwin, Newman, William, Ophoff, Roel A, Papi, Laura, Palmieri, Orazio, Peyrin-Biroulet, Laurent, Panés, Julián, Phillips, Anne, Prescott, Natalie J, Proctor, Deborah D, Roberts, Rebecca, Russell, Richard, Rutgeerts, Paul, Sanderson, Jeremy, Sans, Miquel, Schumm, Philip, Seibold, Frank, Sharma, Yashoda, Simms, Lisa A, Seielstad, Mark, Steinhart, A Hillary, Targan, Stephan R, van den Berg, Leonard H, Vatn, Morten, Verspaget, Hein, Walters, Thomas, Wijmenga, Cisca, Wilson, David C, Westra, Harm-Jan, Xavier, Ramnik J, Zhao, Zhen Z, Ponsioen, Cyriel Y, Andersen, Vibeke, Torkvist, Leif, Gazouli, Maria, Anagnou, Nicholas P, Karlsen, Tom H, Kupcinskas, Limas, Sventoraityte, Jurgita, Mansfield, John C, Kugathasan, Subra, Silverberg, Mark S, Halfvarson, Jonas, Rotter, Jerome I, Mathew, Christopher G, Griffiths, Anne M, Gearry, Richard, Ahmad, Tariq, Brant, Steven R, and Chamaillard, Mathias

Subjects
Biological Sciences, Genetics, Autoimmune Disease, Human Genome, Crohn's Disease, Digestive Diseases, Nutrition, Inflammatory Bowel Disease, Prevention, Oral and gastrointestinal, Colitis, Ulcerative, Crohn Disease, Genome-Wide Association Study, Humans, Risk, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Published
2011

7. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Author

Eijsbouts, Chris, Zheng, Tenghao, Kennedy, Nicholas A., Bonfiglio, Ferdinando, Anderson, Carl A., Moutsianas, Loukas, Holliday, Joanne, Shi, Jingchunzi, Shringarpure, Suyash, Voda, Alexandru-Ioan, Farrugia, Gianrico, Franke, Andre, H��benthal, Matthias, Abecasis, Gon��alo, Zawistowski, Matthew, Skogholt, Anne Heidi, Ness-Jensen, Eivind, Hveem, Kristian, Esko, T��nu, Teder-Laving, Maris, Zhernakova, Alexandra, Camilleri, Michael, Boeckxstaens, Guy, Whorwell, Peter J., Spiller, Robin, McVean, Gil, D���Amato, Mauro, Jostins, Luke, Parkes, Miles, Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., Luff, Marie K., McCreight, Jey C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., Northover, Carrie A. M., O���Connell, Jared, Petrakovitz, Aaron A., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shastri, Anjali J., Shelton, Janie F., Tian, Chao, Tung, Joyce Y., Tunney, Robert J., Vacic, Vladimir, Wang, Xin, Zare, Amir S., Kashyap, Purna, Chang, Lin, Mayer, Emeran, Heitkemper, Margaret, Sayuk, Gregory S., Ringel-Kulka, Tamar, Ringel, Yehuda, Chey, William D., Eswaran, Shanti, Merchant, Juanita L., Shulman, Robert J., Bujanda, Luis, Garcia-Etxebarria, Koldo, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Walter, Susanna, Faresj��, ��shild O., Simren, Magnus, Halfvarson, Jonas, Portincasa, Piero, Barbara, Giovanni, Usai-Satta, Paolo, Neri, Matteo, Nardone, Gerardo, Cuomo, Rosario, Galeazzi, Francesca, Bellini, Massimo, Latiano, Anna, Houghton, Lesley, Jonkers, Daisy, Kurilshikov, Alexander, Weersma, Rinse K., Netea, Mihai, Tesarz, Jonas, Gauss, Annika, Goebel-Stengel, Miriam, Andresen, Viola, Frieling, Thomas, Pehl, Christian, Schaefert, Rainer, Niesler, Beate, Lieb, Wolfgang, Hanevik, Kurt, Langeland, Nina, Wensaas, Knut-Arne, Litleskare, Sverre, Gabrielsen, Maiken E., Thomas, Laurent, Thijs, Vincent, Lemmens, Robin, Van Oudenhove, Lukas, Wouters, Mira, Eijsbouts C., Zheng T., Kennedy N.A., Bonfiglio F., Anderson C.A., Moutsianas L., Holliday J., Shi J., Shringarpure S., Agee M., Aslibekyan S., Auton A., Bell R.K., Bryc K., Clark S.K., Elson S.L., Fletez-Brant K., Fontanillas P., Furlotte N.A., Gandhi P.M., Heilbron K., Hicks B., Hinds D.A., Huber K.E., Jewett E.M., Jiang Y., Kleinman A., Lin K.-H., Litterman N.K., Luff M.K., McCreight J.C., McIntyre M.H., McManus K.F., Mountain J.L., Mozaffari S.V., Nandakumar P., Noblin E.S., Northover C.A.M., O'Connell J., Petrakovitz A.A., Pitts S.J., Poznik G.D., Sathirapongsasuti J.F., Shastri A.J., Shelton J.F., Tian C., Tung J.Y., Tunney R.J., Vacic V., Wang X., Zare A.S., Voda A.-I., Kashyap P., Chang L., Mayer E., Heitkemper M., Sayuk G.S., Ringel-Kulka T., Ringel Y., Chey W.D., Eswaran S., Merchant J.L., Shulman R.J., Bujanda L., Garcia-Etxebarria K., Dlugosz A., Lindberg G., Schmidt P.T., Karling P., Ohlsson B., Walter S., Faresjo A.O., Simren M., Halfvarson J., Portincasa P., Barbara G., Usai-Satta P., Neri M., Nardone G., Cuomo R., Galeazzi F., Bellini M., Latiano A., Houghton L., Jonkers D., Kurilshikov A., Weersma R.K., Netea M., Tesarz J., Gauss A., Goebel-Stengel M., Andresen V., Frieling T., Pehl C., Schaefert R., Niesler B., Lieb W., Hanevik K., Langeland N., Wensaas K.-A., Litleskare S., Gabrielsen M.E., Thomas L., Thijs V., Lemmens R., Van Oudenhove L., Wouters M., Farrugia G., Franke A., Hubenthal M., Abecasis G., Zawistowski M., Skogholt A.H., Ness-Jensen E., Hveem K., Esko T., Teder-Laving M., Zhernakova A., Camilleri M., Boeckxstaens G., Whorwell P.J., Spiller R., McVean G., D'Amato M., Jostins L., Parkes M., Eijsbouts, Chris [0000-0001-5179-0653], Anderson, Carl A. [0000-0003-1719-7009], Moutsianas, Loukas [0000-0001-5453-345X], Holliday, Joanne [0000-0003-4568-7320], Shringarpure, Suyash [0000-0001-6464-2668], Voda, Alexandru-Ioan [0000-0003-2974-6992], Farrugia, Gianrico [0000-0003-3473-5235], Hübenthal, Matthias [0000-0002-5956-3006], Abecasis, Gonçalo [0000-0003-1509-1825], Zawistowski, Matthew [0000-0002-3005-083X], Ness-Jensen, Eivind [0000-0001-6005-0729], Teder-Laving, Maris [0000-0002-5872-1850], Camilleri, Michael [0000-0001-6472-7514], Whorwell, Peter J. [0000-0002-5220-8474], Spiller, Robin [0000-0001-6371-4500], McVean, Gil [0000-0002-5012-4162], D’Amato, Mauro [0000-0003-2743-5197], Jostins, Luke [0000-0002-2475-3969], Parkes, Miles [0000-0002-6467-0631], Apollo - University of Cambridge Repository, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Eijsbouts, C., Zheng, T., Kennedy, N. A., Bonfiglio, F., Anderson, C. A., Moutsianas, L., Holliday, J., Shi, J., Shringarpure, S., Agee, M., Aslibekyan, S., Auton, A., Bell, R. K., Bryc, K., Clark, S. K., Elson, S. L., Fletez-Brant, K., Fontanillas, P., Furlotte, N. A., Gandhi, P. M., Heilbron, K., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Lin, K. -H., Litterman, N. K., Luff, M. K., Mccreight, J. C., Mcintyre, M. H., Mcmanus, K. F., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., Northover, C. A. M., O'Connell, J., Petrakovitz, A. A., Pitts, S. J., Poznik, G. D., Sathirapongsasuti, J. F., Shastri, A. J., Shelton, J. F., Tian, C., Tung, J. Y., Tunney, R. J., Vacic, V., Wang, X., Zare, A. S., Voda, A. -I., Kashyap, P., Chang, L., Mayer, E., Heitkemper, M., Sayuk, G. S., Ringel-Kulka, T., Ringel, Y., Chey, W. D., Eswaran, S., Merchant, J. L., Shulman, R. J., Bujanda, L., Garcia-Etxebarria, K., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Walter, S., Faresjo, A. O., Simren, M., Halfvarson, J., Portincasa, P., Barbara, G., Usai-Satta, P., Neri, M., Nardone, G., Cuomo, R., Galeazzi, F., Bellini, M., Latiano, A., Houghton, L., Jonkers, D., Kurilshikov, A., Weersma, R. K., Netea, M., Tesarz, J., Gauss, A., Goebel-Stengel, M., Andresen, V., Frieling, T., Pehl, C., Schaefert, R., Niesler, B., Lieb, W., Hanevik, K., Langeland, N., Wensaas, K. -A., Litleskare, S., Gabrielsen, M. E., Thomas, L., Thijs, V., Lemmens, R., Van Oudenhove, L., Wouters, M., Farrugia, G., Franke, A., Hubenthal, M., Abecasis, G., Zawistowski, M., Skogholt, A. H., Ness-Jensen, E., Hveem, K., Esko, T., Teder-Laving, M., Zhernakova, A., Camilleri, M., Boeckxstaens, G., Whorwell, P. J., Spiller, R., Mcvean, G., D'Amato, M., Jostins, L., and Parkes, M.

Subjects
Male, Molecular Chaperone, Mood Disorder, 631/208/205/2138, Biology, 692/699/1503/1502/2071, Bioinformatics, Polymorphism, Single Nucleotide, Genetic pathways, 38/43, Irritable Bowel Syndrome, Cytoskeletal Protein, Genetics, medicine, Genetic predisposition, Aged, Anxiety Disorders, CD56 Antigen, Cell Adhesion Molecules, Cytoskeletal Proteins, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Homeodomain Proteins, Humans, Middle Aged, Molecular Chaperones, Mood Disorders, United Kingdom, Polymorphism, 692/699/476, Irritable bowel syndrome, Depression (differential diagnoses), article, Homeodomain Protein, Single Nucleotide, Guanine Nucleotide Exchange Factor, medicine.disease, Neuroticism, Biobank, Mood, Cell Adhesion Molecule, Anxiety, medicine.symptom, Anxiety Disorder, Human
Abstract

Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.

Published
2021

8. Crohn’s Disease Is Associated With Activation of Circulating Innate Lymphoid Cells

Author

Mazzurana, Luca, Bonfiglio, Ferdinando, Forkel, Marianne, D’Amato, Mauro, Halfvarson, Jonas, and Mjösberg, Jenny

Subjects
Inflammation, innate lymphoid cells, Immunity, Innate, Crohn's disease, ILC, Crohn Disease, NKp44, Humans, Colitis, Ulcerative, Lymphocytes, Ibdjnl/4, Basic Science Research, SLAMF1, Biomarkers, AcademicSubjects/MED00260, ulcerative colitis, Genome-Wide Association Study
Abstract

Background Inflammatory bowel disease (IBD) is associated with disturbed mucosal innate lymphoid cell (ILC) composition, which is correlated to the degree of intestinal inflammation. However, it remains unclear whether circulating ILCs are dysregulated in patients with IBD. Methods Blood samples from 53 patients with Crohn's disease (CD), 43 patients with ulcerative colitis (UC), and 45 healthy control subjects (HC) were analyzed by flow cytometry for markers of ILC subsets (ILC1, ILC2, and ILC precursors [ILCp]) and selected IBD-relevant proteins, as predicted by previous genome-wide association studies. A dimensionality reduction approach to analyzing the data was used to characterize circulating ILCs. Results The frequency of ILCp expressing the ILC3 activation markers NKp44 and CD56 was increased in CD versus HC and UC (NKp44) or in CD versus HC (CD56), whereas the CD45RA+ ILCp were reduced in CD versus UC. Furthermore, the activation marker HLA-DR was increased on ILC1 and ILC2 in CD versus HC. Interestingly, the IBD-related protein SLAMF1 was upregulated on ILC2 from both CD and UC samples as compared with HC samples. In active CD, SLAMF1+ ILC2 frequency was negatively correlated with disease severity (Harvey-Bradshaw index). The characterization of SLAMF1+ ILC2 revealed a higher expression of the ILC2 markers CRTH2, CD161, and GATA3 as compared with SLAMF1- ILC2. Conclusions In line with the systemic nature of CD inflammation, our findings point toward the activation of ILCs in the blood of patients with CD. Furthermore, in active CD, circulating SLAMF1+ ILC2 are increased in patients with less active disease, introducing SLAMF1+ ILC2 as interesting therapeutic targets deserving further exploration.

Published
2020

9. Detailed Transcriptional Landscape of Peripheral Blood Points to Increased Neutrophil Activation in Treatment-Naive Inflammatory Bowel Disease

Author

Juzenas, Simonas, Hübenthal, Matthias, Lindqvist, Carl Mårten, Kruse, Robert, Steiert, Tim Alexander, Degenhardt, Frauke, Schulte, Dominik, Nikolaus, Susanna, Zeissig, Sebastian, Bergemalm, Daniel, Almer, Sven, Hjortswang, Henrik, Bresso, Francesca, Strüning, Nina, Kupcinskas, Juozas, Keller, Andreas, Lieb, Wolfgang, Rosenstiel, Philip, Schreiber, Stefan, DAmato, Mauro, Halfvarson, Jonas, Hemmrich-Stanisak, Georg, and Franke, Andre

Subjects
Gastroenterology, General Medicine, Gastroenterology and Hepatology, Inflammatory Bowel Diseases, Inflammatory bowel disease, peripheral blood, gene expression, Neutrophil Activation, MicroRNAs, Crohn Disease, Gastroenterologi, Humans, Colitis, Ulcerative, RNA, Messenger, Transcriptome
Abstract

Background and Aims Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohns disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. Methods Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naive [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. Results Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naive IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. Conclusions Immune dysregulation seen in peripheral blood transcriptomes of treatment-naive IBD patients is mainly driven by neutrophil activation. Funding Agencies|European UnionEuropean Commission [733100]; German Research Foundation (DFG) Excellence Cluster Precision Medicine in Chronic Inflammation [PMI]German Research Foundation (DFG) [EXC 2167]; Swedish Foundation for Strategic Research [BIO IBD] [RB13-0160]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-02021]

Published
2022

10. Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort:an Epi-IBD study

Author

Vind, Ida, Thorsgaard, Niels, Salupere, Riina, Olsen, Jongero, Nielsen, Kari Rubek, Oksanen, Pia, Collin, Pekka, Katsanos, Konstantinnos H., Christodoulou, Dimitrios K., Skamnelos, Alexandros, Politis, Dimitrios, Ladefoged, Karin, Lakatos, Peter Laszlo, Végh, Zsuzsanna, Lakatos, Laszlo, Demenyi, Peterne, Kramli, Szabina Nemethne, O'Morain, Colm, Dal Piaz, Giualia, Santini, Alessia, Girardin, Giulia, d'Inca, Renata, Schwartz, Doron, Odes, Selwyn, Kupcinskas, Limas, Jonaitis, Laimas, Kiudelis, Gediminas, Valantiene, Irena, Grp, Epi-Ibd, Burisch, Johan, Kievit, Hendrika Adriana Linda, Andersen, Karina Winther, Andersen, Vibeke, Pedersen, Natalia, Kjeldsen, Jens, Valpiani, Daniela, Toca, Alina, Turcan, Svetlana, Katsanos, Konstantinos H., Fumery, Mathurin, Gower-Rousseau, Corinne, Zammit, Stefania Chetcuti, Ellul, Pierre, Eriksson, Carl, Halfvarson, Jonas, Magro, Fernando Jose, Duricova, Dana, Bortlik, Martin, Fernández, Alberto, Hernandez, Vicent, Myers, Sally, Sebastian, Shaji, Goldis, Adrian, Misra, Ravi, Arebi, Naila, Kaimakliotis, Ioannis P., Nikuina, Inna, Belousova, Elena, Brinar, Marko, Cukovic-Cavka, Silvija, Langholz, Ebbe, Munkholm, Pia, Niewiadomski, Ola, Bell, Sally, Turk, Niksa, Kaimakliotis, Ioannis, Nicolaou, Anastasia, Lukas, Milan, Shonova, Olga, Blichfeldt, Birgitte, Marker, Dorte, Carlsen, Katrine, Weimers, Petra, Aalykke, Clays, Dahlerup, Jens Frederik, Kudsk, Karen, Queen Ingrid's Hospital, Nuuk, Greenland, University of Edinburgh, Trinity College Dublin, Lithuanian University of Health Sciences [Kaunas, Lithuania], CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Registre EPIMAD, CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Örebro University Hospital [Örebro, Sweden], IBD clinical and research centre, ISCARE, Prague, Czech Republic, Universidad Rey Juan Carlos [Madrid] (URJC), Hull and East Yorkshire Eye Hospital, Timisoara Hospital [Timisoara, Romania], Macquarie University, University of Copenhagen = Københavns Universitet (UCPH), Charles University [Prague] (CU), Gastro-Immuno Research Laboratory (GIRL), Dep. V, Hepatology and Gastroenterology, and Aarhus University Hospital

Subjects
Male, 0301 basic medicine, Pediatrics, AZATHIOPRINE, crohn's disease, [SDV]Life Sciences [q-bio], medicine.medical_treatment, CLINICAL-COURSE, Severity of Illness Index, Inflammatory bowel disease, CONVENTIONAL MANAGEMENT, Cohort Studies, 0302 clinical medicine, Crohn Disease, Neoplasms, Epidemiology, HISTORY, Medicine, Prospective Studies, Prospective cohort study, Colectomy, education.field_of_study, Crohn's disease, Gastroenterology, Middle Aged, Prognosis, Europe, Hospitalization, Cohort, Disease Progression, Female, 030211 gastroenterology & hepatology, epidemiology, surgery for Ibd, Cohort study, Adult, medicine.medical_specialty, Population, SURGERY RATES, Young Adult, 03 medical and health sciences, Humans, Immunologic Factors, education, Glucocorticoids, METAANALYSIS, business.industry, medicine.disease, EARLY COMBINED IMMUNOSUPPRESSION, 030104 developmental biology, HOSPITALIZATIONS, business, Intestinal Obstruction, MEDICAL-MANAGEMENT, Follow-Up Studies, INFLAMMATORY-BOWEL-DISEASE
Abstract

ObjectiveThe Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD).DesignPatients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.ResultsIn total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, PConclusionDespite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.

Published
2019

11. Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease

Author

Heap, Graham A., So, Kenji, Weedon, Mike, Edney, Naomi, Bewshea, Claire, Singh, Abhey, Annese, Vito, Beckly, John, Buurman, Dorien, Chaudhary, Rakesh, Cole, Andrew T., Cooper, Sheldon C., Creed, Tom, Cummings, Fraser, de Boer, Nanne K., D'Inca, Renata, D'Souza, Richard, Daneshmend, Tawfique K., Delaney, Michael, Dhar, Anjan, Direkze, Natalie, Dunckley, Paul, Gaya, Daniel R., Gearry, Richard, Gore, Steve, Halfvarson, Jonas, Hart, Ailsa, Hawkey, Chris J., Hoentjen, Frank, Iqbal, Tariq, Irving, Peter, Lal, Simon, Lawrence, Ian, Lees, Charlie W., Lewis, Steve, Lockett, Melanie, Mann, Stephen, Mansfield, John, Mowat, Craig, Mulgrew, Chris J., Müller, Frank, Murray, Charles, Oram, Richard, Orchard, Tim, Parkes, Miles, Phillips, Rosemary, Pollok, Richard, Radford-Smith, Graham, Sebastian, Shaji, Sen, Sandip, Shirazi, Tarek, Silverberg, Mark, Solomon, Laurie, Sturniolo, Giacomo C., Thomas, Mark, Tremelling, Mark, Tsianos, Epameinondas V., Watts, David, Weaver, Sean, Weersma, Rinse K., Wesley, Emma, Holden, Arthur, Ahmad, Tariq, Gastroenterology and hepatology, AGEM - Digestive immunity, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
0301 basic medicine, Male, Interstitial nephritis, medicine.medical_treatment, stratified medicine, GRANULOMATOUS INTERSTITIAL NEPHRITIS, SUSCEPTIBILITY, Kidney, chemistry.chemical_compound, 0302 clinical medicine, TUBULOINTERSTITIAL NEPHRITIS, HLA Antigens, 5-Aminosalicylates, Child, Mesalamine, MANIFESTATION, MESALAZINE, nephrotoxicity, Anti-Inflammatory Agents, Non-Steroidal, Gastroenterology, Acute kidney injury, General Medicine, Acute Kidney Injury, Middle Aged, CROHNS-DISEASE, Phenotype, ULCERATIVE-COLITIS, 030211 gastroenterology & hepatology, Female, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Adult, medicine.medical_specialty, Adolescent, Genotype, RENAL-FAILURE, Renal function, renal failure pharmacogenetics, Nephrotoxicity, 03 medical and health sciences, Young Adult, Mesalazine, Internal medicine, medicine, Humans, LITHIUM, Renal replacement therapy, GENOME-WIDE ASSOCIATION, Aged, ulcerative colitis, Creatinine, business.industry, Odds ratio, DNA, medicine.disease, Inflammatory Bowel Diseases, 030104 developmental biology, chemistry, Immunology, business, Genome-Wide Association Study
Abstract

Background and Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, >= 50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls.Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1 x 10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4 x 10(-9), odds ratio 3.1).Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

Published
2016

12. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Author

Goyette, Philippe, Boucher, Gabrielle, Mallon, Dermot, Ellinghaus, Eva, Jostins, Luke, Huang, Hailiang, Ripke, Stephan, Gusareva, Elena S., Annese, Vito, Hauser, Stephen L., Oksenberg, Jorge R., Thomsen, Ingo, Leslie, Stephen, Daly, Mark J., Van Steen, Kristel, Duerr, Richard H., Barrett, Jeffrey C., Mcgovern, Dermot P. B., Schumm, L. Philip, Traherne, James A., Carrington, Mary N., Kosmoliaptsis, Vasilis, Karlsen, Tom H., Franke, Andre, Rioux, John D., Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Balschun, Tobias, Bampton, Peter A., Barclay, Murray, Bayless, Theodore M., Bethge, Johannes, Bis, Joshua C., Bitton, Alain, Brand, Stephan, Brant, Steven R., Buning, Carsten, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Croft, Anthony, D'Amato, Mauro, Danese, Silvio, De Jong, Dirk, De Vos, Martine, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jurgen, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Xinli, Hu, Hui, Ken Y., Imielinski, Marcin, Ippoliti, Andrew, Jonaitis, Laimas, Kennedy, Nicholas A., Khan, Mohammed Azam, Kiudelis, Gediminas, Kugathasan, Subra, Kupcinskas, Limas, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Mahy, Gillian, Mansfield, John, Massey, Dunecan, Mathew, Christopher G., Milgrom, Raquel, Mitrovic, Mitja, Montgomery, Grant, Mowat, Craig, Newman, Wwilliam, Aylwin, Ng, Siew C., Ng, Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nothen, Markus, Oikonomou, Ioannis, Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Proctor, Deborah D., Radford Smith, Graham, Rahier, Jean Francois, Raychaudhur, Soumya, Regueiro, Miguel, Rieder, Florian, Roberts, Rebecca, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Schreiber, Stefan, Scott, Regan, Seielstad, Mark, Sharma, Yashoda, Silverberg, Mark S., Simms, Lisa A., Skieceviciene, Jurgita, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kirstin M., Ter Velde, Anje, Theatre, Emilie, Torkvist, Leif, Tremelling, Mark, Van Der Meulen, Andrea, Van Sommeren, Suzanne, Vasiliauskas, Eric, Vermeire, Severine, Verspaget, Hein W., Walters, Thomas, Wwang, Kai, Wwang, Ming Hsi, Wweersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wwei, Zhao, Hongyu, Zhao, Zhen Z., Gastroenterology and Hepatology, Traherne, James [0000-0002-6003-8559], Kosmoliaptsis, Vasilis [0000-0001-7298-1387], and Apollo - University of Cambridge Repository

Subjects
Heterozygote, Genotype, Genotyping Techniques, Genetic Linkage, Ulcerative, Human leukocyte antigen, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, Major Histocompatibility Complex, Alleles, Chromosome Mapping, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB1 Chains, Humans, Inflammatory Bowel Diseases, Phenotype, Genetics, medicine, HLA-DR, Polymorphism, Colitis, HLA-DRB1, Crohn's disease, Single Nucleotide, medicine.disease, Ulcerative colitis, digestive system diseases, Immunology, biology.protein
Abstract

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Published
2015

13. Stress resilience and the risk of inflammatory bowel disease: a cohort study of men living in Sweden

Author

Melinder, Carren, Hiyoshi, Ayako, Fall, Katja, Halfvarson, Jonas, and Montgomery, Scott

Subjects
Adult, Male, Risk, Sweden, Adolescent, Epidemiology, Research, Men, Blood Sedimentation, Middle Aged, Resilience, Psychological, GASTROENTEROLOGY, Inflammatory Bowel Diseases, Cohort Studies, Young Adult, Crohn Disease, Humans, Colitis, Ulcerative, Registries, Stress, Psychological
Abstract

Objective To determine if low psychosocial stress resilience in adolescence (increasing chronic stress arousal throughout life) is associated with an increased inflammatory bowel disease (IBD) risk in adulthood. Subclinical Crohn's disease (CD) and ulcerative colitis (UC) can exist over many years and we hypothesise that psychosocial stress may result in conversion to symptomatic disease through its proinflammatory or barrier function effects. Design National register-based cohort study of men followed from late adolescence to middle age. Setting A general population cohort of men in Sweden. Participants Swedish population-based registers provided information on all men born between 1952 and 1956 who underwent mandatory Swedish military conscription assessment (n=239 591). Men with any gastrointestinal diagnoses (except appendicitis) prior to follow-up were excluded. Primary outcome measures An inpatient or outpatient diagnosis of CD or UC recorded in the Swedish Patient Register (1970–2009). Results A total of 938 men received a diagnosis of CD and 1799 UC. Lower stress resilience in adolescence was associated with increased IBD risk, with unadjusted HRs (95% CIs) of 1.54 (1.26 to 1.88) and 1.24 (1.08 to 1.42), for CD and UC, respectively. After adjustment for potential confounding factors, including markers of subclinical disease activity in adolescence, they are 1.39 (1.13 to 1.71) and 1.19 (1.03 to 1.37). Conclusions Lower stress resilience may increase the risk of diagnosis of IBD in adulthood, possibly through an influence on inflammation or barrier function.

Published
2017

14. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author

Rivas, Manuel A, Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, A Nicole, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Sören, Kurki, Mitja I, Li, Dalin, D'Amato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse K, Halfvarson, Jonas, Paavola-Sakki, Paulina, Lappalainen, Maarit, Lek, Monkol, Cummings, Beryl, Tukiainen, Taru, Haritunians, Talin, Halme, Leena, Koskinen, Lotta LE, Ananthakrishnan, Ashwin N, Luo, Yang, Heap, Graham A, Visschedijk, Marijn C, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, MacArthur, Daniel G, Neale, Benjamin M, Ahmad, Tariq, Anderson, Carl A, Brant, Steven R, Duerr, Richard H, Silverberg, Mark S, Cho, Judy H, Palotie, Aarno, Saavalainen, Päivi, Kontula, Kimmo, Färkkilä, Martti, McGovern, Dermot PB, Franke, Andre, Stefansson, Kari, Rioux, John D, Xavier, Ramnik J, Daly, Mark J, Barrett, J, De Lane, K, Edwards, C, Hart, A, Hawkey, C, Jostins, L, Kennedy, N, Lamb, C, Lee, J, Lees, C, Mansfield, J, Mathew, C, Mowatt, C, Newman, B, Nimmo, E, Parkes, M, Pollard, M, Prescott, N, Randall, J, Rice, D, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, D, Abraham, C, Achkar, JP, Bitton, A, Boucher, G, Croitoru, K, Fleshner, P, Glas, J, Kugathasan, S, Limbergen, JV, Milgrom, R, Proctor, D, Regueiro, M, Schumm, PL, Sharma, Y, Stempak, JM, Targan, Wang, MH, Sulem, Patrick [0000-0001-7123-6123], Gudbjartsson, Daniel [0000-0002-5222-9857], Heap, Graham A [0000-0003-4131-6792], Neale, Benjamin M [0000-0003-1513-6077], Duerr, Richard H [0000-0001-6586-3905], Daly, Mark J [0000-0002-0949-8752], and Apollo - University of Cambridge Repository

Subjects
Protein Transport, Ubiquitin-Protein Ligases, Mutation, Humans, Reproducibility of Results, Colitis, Ulcerative, Genetic Predisposition to Disease, Genetic Testing, RNA, Messenger, Sequence Analysis, DNA, Alleles, Genetic Association Studies
Abstract

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.

Published
2016

15. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes:a genetic association study

Author

Cleynen, Isabelle, Boucher, Gabrielle, Jostins, Luke, Schumm, L. Philip, Zeissig, Sebastian, Ahmad, Tariq, Andersen, Vibeke, Andrews, Jane M., Annese, Vito, Brand, Stephan, Brant, Steven R., Cho, Judy H., Daly, Mark J., Dubinsky, Marla, Duerr, Richard H., Ferguson, Lynnette R., Franke, Andre, Gearry, Richard B., Goyette, Philippe, Hakonarson, Hakon, Halfvarson, Jonas, Hov, Johannes R., Huang, Hailang, Kennedy, Nicholas A., Kupcinskas, Limas, Lawrance, Ian C., Lee, James C., Satsangi, Jack, Schreiber, Stephan, Théâtre, Emilie, Van Der Meulen De Jong, Andrea E, Weersma, Rinse K., Wilson, David C., Parkes, Miles, Vermeire, Severine, Rioux, John D., Mansfield, John, Silverberg, Mark S., Radford Smith, Graham, Mcgovern, Dermot P. B., Barrett, Jeffrey C., Lees, Charlie W, Abraham, C, Achkar, Jp, Ahmad, T, Amininejad, L, Ananthakrishnan, An, Andersen, V, Anderson, Ca, Andrews, Jm, Annese, V, Aumais, G, Baidoo, L, Baldassano, Rn, Bampton, Pa, Barclay, M, Barrett, Jc, Bayless, Tm, Bethge, J, Bis, Jc, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Büning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, De Vos, M, Denapiene, G, Denson, La, Devaney, K, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franchimont, D, Franke, A, Fransen, K, Gearry, R, Georges, M, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, Am, Guthery, Sl, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, Hart, A, Hawkey, C, Hayward, Nk, Hedl, M, Henderson, P, Hu, X, Huang, H, Hui, Ky, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, Th, Kennedy, Na, Khan, Ma, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, Ic, Lee, Jc, Lees, Cw, Leja, M, Van Limbergen, J, Lionetti, P, Liu, Jz, Louis, E, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dp, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sm, Nikolaus, S, Ning, K, Nöthen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, Cy, Potocnik, U, Prescott, Nj, Proctor, Dd, Radford Smith, G, Rahier, Jf, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, Jd, Ripke, S, Roberts, R, Russell, Rk, Sanderson, Jd, Sans, M, Satsangi, J, Schadt, Ee, Schreiber, S, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, Ms, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, A, Stempak, Jm, Stronati, Laura, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Theatre, E, Torkvist, L, Tremelling, M, van der Meulen, A, van Sommeren, S, Vasiliauskas, E, Vermeire, S, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Weersma, Rk, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zeissig, S, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, H, Zhao, Zz, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, 0301 basic medicine, CLINICAL-COURSE, Nod2 Signaling Adaptor Protein, Disease, SUSCEPTIBILITY, Inflammatory bowel disease, Major Histocompatibility Complex, 0302 clinical medicine, Crohn Disease, Maintenance therapy, NOD2, Medicine and Health Sciences, POPULATION, Immunoassay, RISK, Medicine(all), education.field_of_study, Crohn's disease, Hepatocyte Growth Factor, Medicine (all), INDUCTION, Articles, General Medicine, PRIMARY SCLEROSING CHOLANGITIS, Ulcerative colitis, 3. Good health, Phenotype, Female, 030211 gastroenterology & hepatology, Adult, medicine.medical_specialty, MAINTENANCE THERAPY, Genotype, Population, Polymorphism, Single Nucleotide, Risk Assessment, CLASSIFICATION, Primary sclerosing cholangitis, Young Adult, 03 medical and health sciences, inflammatory bowel disease, Proto-Oncogene Proteins, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Alleles, Genetic Association Studies, business.industry, medicine.disease, digestive system diseases, 030104 developmental biology, Immunology, Colitis, Ulcerative, business, FOLLOW-UP, HLA-DRB1 Chains, INFLAMMATORY-BOWEL-DISEASE
Abstract

Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Published
2016

16. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis

Author

Beaudoin, Melissa, Goyette, Philippe, Goel, Gautam, Louis, E., Mansfield, J. C., Mathew, C. G., McGovern, D. P., Mitrovic, M., Montgomery, G. W., Mowat, C., Newman, W., Palmieri, O., Panés, J., Lagace, Caroline, Parkes, M., Phillips, A., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Proctor, D. D., Radford-Smith, G. L., Regueiro, M., Rioux, J. D., Roberts, R., Annese, Vito, Rotter, J. I., Rutgeerts, P., Sanderson, J., Sans, M., Satsangi, J., Schreiber, S., Schumm, P., Seibold, F., Sharma, Y., Silverberg, M. S., Bitton, Alain, Simms, L. A., Steinhart, A., Targan, S. R., Taylor, K. D., Torkvist, L., Vermeire, S., Halfvarson, J., Verspaget, H. W., De Vos, M., Walters, T., Begun, Jakob, Wang, K., Weersma, R. K., Whiteman, D., Wijmenga, C., Brant, Steven R., Bresso, Francesca, Cho, Judy H., Duerr, Richard H., Halfvarson, Jonas, Boucher, Gabrielle, McGovern, Dermot P. B., Radford-Smith, Graham, Schreiber, Stefan, Schumm, Philip L., Sharma, Yashoda, Silverberg, Mark S., Weersma, Rinse K., Quebec IBD Genetics Consortium, NIDDK IBD Genetics Consortium, International IBD Genetics Consortium (IIBDGC), Lo, Ken Sin, D'Amato, Mauro, Vermeire, Severine, Franke, Andre, Lettre, Guillaume, Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Aumais, G., Bernard, E. J., Bitton, A., Rivas, Manuel A., Cohen, A., Deslandres, C., Lahaie, R., Paré, P., Brant, S. R., Cho, J. H., Duerr, R. H., Stevens, Christine, Ahmad, T., Anderson, C. A., Annese, V., Baldassano, R. N., Balschun, T., Barclay, M., Barrett, J. C., Bayless, T. M., Bis, J. C., Alikashani, Azadeh, Brand, S., Bumpstead, S., Buning, C., Colombel, J. F., Cottone, M., D'Amato, M., D'Inca, R., Ladouceur, Martin, Daly, M. J., Denson, T., Dubinsky, M., Edwards, C., Ellinghaus, D., Florin, T., Franchimont, D., Franke, A., Gearry, R., Ellinghaus, David, Georges, M., Glas, J., Van Gossum, A., Griffiths, A. M., Guthery, S. L., Hakonarson, H., Haritunians, T., Hugot, J. P., de Jong, D. J., Jostins, L., Torkvist, Leif, Kugathasan, S., Kullak-Ublick, G., Latiano, A., Laukens, D., Lawrance, I., Lee, J., Lees, C. W., Lemann, M., Levine, A., Libioulle, C., and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Cancer Research, Génétique clinique, LIVER, Genome-wide association study, Inflammatory bowel disease, 0302 clinical medicine, Crohn Disease, GENETIC-VARIANTS, Medicine and Health Sciences, Ethnicity, UBIQUITIN LIGASES, Genetics(clinical), Genetics (clinical), Genetics, 0303 health sciences, Ecology, High-Throughput Nucleotide Sequencing, CROHN-DISEASE, CROHNS-DISEASE, 3. Good health, 030220 oncology & carcinogenesis, Medical genetics, Biologie, Research Article, EXPRESSION, medicine.medical_specialty, Canada, lcsh:QH426-470, SUSCEPTIBILITY LOCI, Evolution, Ubiquitin-Protein Ligases, Ethnic Groups, Evolution des espèces, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], Polymorphism, Single Nucleotide, 03 medical and health sciences, Behavior and Systematics, medicine, Humans, Genetic Predisposition to Disease, Ligase activity, MODULATION, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Genotyping, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, Ecologie, Biologie moléculaire, Receptors, Interleukin, medicine.disease, NUCLEAR FACTOR 4-ALPHA, Genetic architecture, Cancérologie, CARD Signaling Adaptor Proteins, lcsh:Genetics, CELLS, Colitis, Ulcerative, INTESTINAL EPITHELIAL-CELLS, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013

17. Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study

Author

Burisch, Johan Michael, Cukovic-Cavka, Silvija, Kaimakliotis, Ioannis, Shonová, Olga, Andersen, Vibeke, Dahlerup, Jens Frederik, Elkjaer, Margarita, Langholz, Ebbe, Pedersen, Eva Natalia G., Salupere, Riina, Kolho, Kaija-Leena, Manninen, Pia, Lakatos, Peter Laszlo, Shuhaibar, Mary, Odes, Selwyn, Martinato, Matteo, Mihu, Ion, Magro, Fernando, Belousova, Elena, Fernandez, Alberto, Almer, Sven, Halfvarson, Jonas, Hart, Ailsa, and Munkholm, Pia

Subjects
Europe, Databases, Factual, web-based epidemiological database, inflammatory bowel disease, Database Management Systems, Humans, Translating, Inflammatory Bowel Diseases
Abstract

The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. Aim was to construct and validate a web-based inception cohort database available in both English and Russian language. The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.

Published
2010

18. Meta-Analysis Increases to 71 the Tally of Confirmed Crohn’s Disease Susceptibility Loci

Author

Franke, Andre, McGovern, Dermot P.B., Barrett, Jeffrey C., Wang, Kai, Radford-Smith, Graham L., Ahmad, Tariq, Lees, Charlie W., Balschun, Tobias, Lee, James, Roberts, Rebecca, Anderson, Carl A., Bis, Joshua C., Bumpstead, Suzanne, Ellinghaus, David, Festen, Eleonora M., Georges, Michel, Haritunians, Talin, Jostins, Luke, Latiano, Anna, Mathew, Christopher G., Montgomery, Grant W., Prescott, Natalie J., Rotter, Jerome I., Schumm, Philip, Sharma, Yashoda, Simms, Lisa A., Taylor, Kent D., Whiteman, David, Wijmenga, Cisca, Baldassano, Robert N., Barclay, Murray, Bayless, Theodore M., Brand, Stephan, Buning, Carsten, Cohen, Albert, Colombel, Jean-Frederick, Cottone, Mario, Stronati, Laura, Denson, Ted, De Vos, Martine, D’Inca, Renata, Dubinsky, Marla, Edwards, Cathryn, Florin, Tim, Franchimont, Denis, Gearry, Richard, Glas, Jürgen, Van Gossum, Andre, Guthery, Stephen L., Halfvarson, Jonas, Hommes, Daan, Hugot, Jean-Pierre, Laukens, Debby, Lawrance, Ian, Lemann, Marc, Levine, Arie, Libioulle, Cecile, Louis, Edouard, Mowat, Craig, Newman, William, Panés, Julián, Phillips, Anne, Proctor, Deborah D., Regueiro, Miguel, Rutgeerts, Paul, Sanderson, Jeremy, Sans, Miquel, Seibold, Frank, Steinhart, A. Hillary, Stokkers, Pieter C.F., Torkvist, Leif, Ublick, Gerd Kullak, Raychaudhuri, Soumya, Green, Todd, Walters, Thomas, Targan, Stephan R., Brant, Steven R., Rioux, John D., D’Amato, Mauro, Weersma, Rinse, Kugathasan, Subra, Griffiths, Anne M., Mansfield, John C., Vermeire, Severine, Duerr, Richard H., Silverberg, Mark S., Satsangi, Jack, Schreiber, Stefan, Cho, Judy H., Annese, Vito, Hakonarson, Hakon, Daly, Mark J., and Parkes, Miles

Subjects
Crohn Disease, Genetic Linkage, Genetic Loci, Genome, Human, Computational Biology, Genetic Variation, Humans, Reproducibility of Results, Genetic Predisposition to Disease, Article, Genome-Wide Association Study
Abstract

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

Published
2010

19. Fine-mapping inflammatory bowel disease loci to single-variant resolution

Author

Huang, Hailiang, Fang, Ming, Jostins, Luke, Umićević Mirkov, Maša, Boucher, Gabrielle, Anderson, Carl A, Andersen, Vibeke, Cleynen, Isabelle, Cortes, Adrian, Crins, François, D'Amato, Mauro, Deffontaine, Valérie, Dmitrieva, Julia, Docampo, Elisa, Elansary, Mahmoud, Farh, Kyle Kai-How, Franke, Andre, Gori, Ann-Stephan, Goyette, Philippe, Halfvarson, Jonas, Haritunians, Talin, Knight, Jo, Lawrance, Ian C, Lees, Charlie W, Louis, Edouard, Mariman, Rob, Meuwissen, Theo, Mni, Myriam, Momozawa, Yukihide, Parkes, Miles, Spain, Sarah L, Théâtre, Emilie, Trynka, Gosia, Satsangi, Jack, Van Sommeren, Suzanne, Vermeire, Severine, Xavier, Ramnik J, International Inflammatory Bowel Disease Genetics Consortium, Weersma, Rinse K, Duerr, Richard H, Mathew, Christopher G, Rioux, John D, McGovern, Dermot PB, Cho, Judy H, Georges, Michel, Daly, Mark J, and Barrett, Jeffrey C

Subjects
Adult, Aged, 80 and over, Male, Binding Sites, Adolescent, Genotype, Quantitative Trait Loci, Genetic Variation, Middle Aged, Inflammatory Bowel Diseases, Chromatin, Linkage Disequilibrium, 3. Good health, Epigenesis, Genetic, Young Adult, Crohn Disease, Humans, Colitis, Ulcerative, Female, Genetic Predisposition to Disease, Smad3 Protein, Aged, Genome-Wide Association Study, Transcription Factors
Abstract

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

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