41 results on '"Giri, Mamta"'
Search Results
2. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.
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Wu, Yiming, Gettler, Kyle, Kars, Meltem, Giri, Mamta, Li, Dalin, Bayrak, Cigdem, Zhang, Peng, Jain, Aayushee, Maffucci, Patrick, Sabic, Ksenija, Van Vleck, Tielman, Nadkarni, Girish, Denson, Lee, Ostrer, Harry, Levine, Adam, Schiff, Elena, Segal, Anthony, Kugathasan, Subra, Stenson, Peter, Cooper, David, Philip Schumm, L, Snapper, Scott, Daly, Mark, Haritunians, Talin, Duerr, Richard, Silverberg, Mark, Rioux, John, Brant, Steven, McGovern, Dermot, Cho, Judy, and Itan, Yuval
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Adult ,Humans ,Jews ,Exome ,Inflammatory Bowel Diseases ,Risk Assessment ,Genetic Predisposition to Disease - Abstract
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.
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- 2023
3. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
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Mo, Angela, Nagpal, Sini, Gettler, Kyle, Haritunians, Talin, Giri, Mamta, Haberman, Yael, Karns, Rebekah, Prince, Jarod, Arafat, Dalia, Hsu, Nai-Yun, Chuang, Ling-Shiang, Argmann, Carmen, Kasarskis, Andrew, Suarez-Farinas, Mayte, Gotman, Nathan, Mengesha, Emebet, Venkateswaran, Suresh, Rufo, Paul A, Baker, Susan S, Sauer, Cary G, Markowitz, James, Pfefferkorn, Marian D, Rosh, Joel R, Boyle, Brendan M, Mack, David R, Baldassano, Robert N, Shah, Sapana, LeLeiko, Neal S, Heyman, Melvin B, Griffiths, Anne M, Patel, Ashish S, Noe, Joshua D, Davis Thomas, Sonia, Aronow, Bruce J, Walters, Thomas D, McGovern, Dermot PB, Hyams, Jeffrey S, Kugathasan, Subra, Cho, Judy H, Denson, Lee A, and Gibson, Greg
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Digestive Diseases ,Inflammatory Bowel Disease ,Human Genome ,Autoimmune Disease ,Clinical Research ,Genetics ,Patient Safety ,Biotechnology ,Prevention ,Generic health relevance ,Biological Specimen Banks ,Cohort Studies ,Colectomy ,Colitis ,Ulcerative ,Colon ,Crohn Disease ,Datasets as Topic ,Disease Progression ,Gene Expression Profiling ,Genome-Wide Association Study ,Humans ,Multifactorial Inheritance ,Prognosis ,Quantitative Trait Loci ,Risk Assessment ,Transcriptome ,United Kingdom ,cell-type-specific gene expression ,eQTLs ,predicted polygenic transcriptional risk scores ,prediction of disease progression ,transcriptional risk scores ,transcriptome-wide association studies ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
- Published
- 2021
4. Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target.
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Chen, Ernie, Chuang, Ling-Shiang, Giri, Mamta, Villaverde, Nicole, Hsu, Nai-Yun, Sabic, Ksenija, Joshowitz, Sari, Gettler, Kyle, Nayar, Shikha, Chai, Zhi, Alter, Isaac, Chasteau, Colleen, Korie, Ujunwa, Dzedzik, Siarhei, Thin, Tin, Jain, Aayushee, Moscati, Arden, Bongers, Gerardus, Duerr, Richard, Silverberg, Mark, Brant, Steven, Rioux, John, Peter, Inga, Schumm, L, Haritunians, Talin, McGovern, Dermot, Itan, Yuval, and Cho, Judy
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G-Protein Coupled Receptors ,Mast Cells ,Single Cell Sequencing ,Ulcerative Colitis ,Adrenomedullin ,Animals ,CHO Cells ,Case-Control Studies ,Cell Degranulation ,Colitis ,Ulcerative ,Colon ,Cricetulus ,Extracellular Signal-Regulated MAP Kinases ,Genetic Variation ,Humans ,Inositol Phosphates ,Ligands ,Mast Cells ,Nerve Tissue Proteins ,Phosphorylation ,Receptors ,G-Protein-Coupled ,Receptors ,Neuropeptide ,beta-Arrestin 2 - Abstract
BACKGROUND & AIMS: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. METHODS: Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase. RESULTS: Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances β-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression. CONCLUSION: Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.
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- 2021
5. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
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Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.
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- 2022
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6. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease
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Nayar, Shikha, Morrison, Joshua K., Giri, Mamta, Gettler, Kyle, Chuang, Ling-shiang, Walker, Laura A., and Ko, Huaibin M.
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NOD2 -- Health aspects ,Crohn's disease -- Genetic aspects -- Development and progression -- Drug therapy ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease.sup.1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment.sup.3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2.sup.4,5, which increase the risk of stricturing.sup.6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14.sup.+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease--potentially as a complement to anti-TNF therapy. NOD2 deficiency drives fibrosis and stricturing complications in Crohn's disease through dysregulated homeostasis of activated fibroblasts and macrophages, which is ameliorated by gp130 blockade in human cell and zebrafish models., Author(s): Shikha Nayar [sup.1] [sup.2] , Joshua K. Morrison [sup.3] , Mamta Giri [sup.4] , Kyle Gettler [sup.1] [sup.4] , Ling-shiang Chuang [sup.1] , Laura A. Walker [sup.5] , Huaibin [...]
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- 2021
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7. Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy.
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Bello, Luca, Flanigan, Kevin, Weiss, Robert, Spitali, Pietro, Aartsma-Rus, Annemieke, Muntoni, Francesco, Zaharieva, Irina, Ferlini, Alessandra, Mercuri, Eugenio, Tuffery-Giraud, Sylvie, Claustres, Mireille, Straub, Volker, Lochmüller, Hanns, Barp, Andrea, Vianello, Sara, Pegoraro, Elena, Punetha, Jaya, Gordish-Dressman, Heather, Giri, Mamta, Hoffman, Eric, and McDonald, Craig
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Adolescent ,Alleles ,CD40 Antigens ,Case-Control Studies ,Child ,Dystrophin ,Exons ,Genes ,Modifier ,Genome-Wide Association Study ,Glucocorticoids ,Humans ,Latent TGF-beta Binding Proteins ,Muscular Dystrophy ,Duchenne ,Mutation ,NF-kappa B ,Osteopontin ,Polymorphism ,Single Nucleotide ,Transforming Growth Factor beta ,White People - Abstract
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.
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- 2016
8. NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures
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Hsu, Nai-Yun, primary, Nayar, Shikha, additional, Gettler, Kyle, additional, Talware, Sayali, additional, Giri, Mamta, additional, Alter, Isaac, additional, Argmann, Carmen, additional, Sabic, Ksenija, additional, Thin, Tin Htwe, additional, Ko, Huai-Bin Mabel, additional, Werner, Robert, additional, Tastad, Christopher, additional, Stappenbeck, Thaddeus, additional, Azabdaftari, Aline, additional, Uhlig, Holm H, additional, Chuang, Ling-Shiang, additional, and Cho, Judy H, additional
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- 2022
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9. NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures.
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Nai-Yun Hsu, Nayar, Shikha, Gettler, Kyle, Talware, Sayali, Giri, Mamta, Alter, Isaac, Argmann, Carmen, Sabic, Ksenija, Tin Htwe Thin, Huai-Bin Mabel Ko, Werner, Robert, Tastad, Christopher, Stappenbeck, Thaddeus, Azabdaftari, Aline, Uhlig, Holm H., Ling-Shiang Chuang, and Cho, Judy H.
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STEM cell niches ,CYTOLOGY ,SECRETION ,INFLAMMATORY bowel diseases ,INTESTINES ,PROTEIN kinases ,HEROIN - Published
- 2023
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10. Single‐cell transcriptomics reveals conserved cell identities and fibrogenic phenotypes in zebrafish and human liver
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Morrison, Joshua K., primary, DeRossi, Charles, additional, Alter, Isaac L., additional, Nayar, Shikha, additional, Giri, Mamta, additional, Zhang, Chi, additional, Cho, Judy H., additional, and Chu, Jaime, additional
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- 2022
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11. Pyruvate Dehydrogenase Phosphatase Regulatory Gene Expression Correlates with Exercise Training Insulin Sensitivity Changes
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BARBERIO, MATTHEW D., HUFFMAN, KIM M., GIRI, MAMTA, HOFFMAN, ERIC P., KRAUS, WILLIAM E., and HUBAL, MONICA J.
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- 2016
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12. A Role for CXCR3 Ligands as Biomarkers of Post-Operative Crohn’s Disease Recurrence
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Walshe, Margaret, primary, Nayeri, Shadi, additional, Ji, Jiayi, additional, Hernandez-Rocha, Cristian, additional, Sabic, Ksenija, additional, Hu, Liangyuan, additional, Giri, Mamta, additional, Nayar, Shikha, additional, Brant, Steven, additional, McGovern, Dermot P B, additional, Rioux, John D, additional, Duerr, Richard H, additional, Cho, Judy H, additional, Schumm, Phil L, additional, Lazarev, Mark, additional, and Silverberg, Mark S, additional
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- 2021
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13. Single-cell transcriptomic profiling of healthy and fibrotic adult zebrafish liver reveals conserved cell identities and stellate cell activation phenotypes with human liver
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Morrison, Joshua K., primary, DeRossi, Charles, additional, Alter, Isaac L., additional, Nayar, Shikha, additional, Giri, Mamta, additional, Zhang, Chi, additional, Cho, Judy H., additional, and Chu, Jaime, additional
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- 2021
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14. 374 INFLAMED ULCERATIVE COLITIS REGIONS ASSOCIATED TO MRGPRX2-MEDIATED MAST CELL DEGRANULATION AND CELL ACTIVATION MODULES, DEFINING A NEW THERAPEUTIC TARGET
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Chuang, Ling-shiang F., primary, Chen, Ernie, additional, Giri, Mamta, additional, Villaverde, Nicole, additional, Hsu, Nai-yun, additional, Sabic, Ksenija, additional, Joshowitz, Sari, additional, Gettler, Kyle, additional, Nayar, Shikha, additional, Chai, Zhi, additional, Alter, Isaac, additional, Chasteau, Colleen, additional, Korie, Ujunwa, additional, Dzedzik, Siarhei, additional, Thin, Tin Htwe, additional, Jain, Aayushee, additional, Moscati, Arden, additional, Bongers, Gerold, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Brant, Steven R., additional, Rioux, John D., additional, Peter, Inga, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, Mcgovern, Dermot P.B., additional, Itan, Yuval, additional, and Cho, Judy H., additional
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- 2021
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15. 168 GENE EXPRESSION ANALYSES IN THE PERIOPERATIVE ILEAL RESECTION PERIOD ILLUMINATE PATHOGENIC AND PROTECTIVE CROHN'S DISEASE CELL SUBSETS
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Gettler, Kyle, primary, Sabic, Ksenija, additional, Giri, Mamta, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, Lazarev, Mark, additional, Mcgovern, Dermot P.B., additional, Duerr, Richard H., additional, Rioux, John D., additional, Brant, Steven R., additional, Silverberg, Mark S., additional, and Cho, Judy H., additional
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- 2021
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16. 776 IDENTIFYING NOVEL HIGH-IMPACT RARE DISEASE-CAUSING MUTATIONS, GENES AND PATHWAYS IN EXOMES OF ASHKENAZI JEWISH INFLAMMATORY BOWEL DISEASE PATIENT
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Wu, Yiming, primary, Gettler, Kyle, additional, Giri, Mamta, additional, Sabic, Ksenija, additional, Schumm, L. Philip, additional, Daly, Mark J., additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Rioux, John D., additional, Brant, Steven R., additional, Mcgovern, Dermot P.B., additional, Cho, Judy H., additional, and Itan, Yuval, additional
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- 2021
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17. NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures
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Hsu, Nai-Yun, Nayar, Shikha, Gettler, Kyle, Talware, Sayali, Giri, Mamta, Alter, Isaac, Argmann, Carmen, Sabic, Ksenija, Thin, Tin Htwe, Ko, Huai-Bin Mabel, Werner, Robert, Tastad, Christopher, Stappenbeck, Thaddeus, Azabdaftari, Aline, Uhlig, Holm H, Chuang, Ling-Shiang, and Cho, Judy H
- Abstract
ObjectiveLoss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined.DesignROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury.ResultsTNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1(DNA methyltransferase) and HIF1A(hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2(glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation.ConclusionsNOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.
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- 2023
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18. Role for CXCR3 Ligands as Biomarkers of Post-Operative Crohn's Disease Recurrence.
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Walshe, Margaret, Nayeri, Shadi, Ji, Jiayi, Hernandez-Rocha, Cristian, Sabic, Ksenija, Hu, Liangyuan, Giri, Mamta, Nayar, Shikha, Brant, Steven, McGovern, Dermot P B, Rioux, John D, Duerr, Richard H, Cho, Judy H, Schumm, Phil L, Lazarev, Mark, and Silverberg, Mark S
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- 2022
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19. Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression
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Mo, Angela, primary, Nagpal, Sini, additional, Gettler, Kyle, additional, Haritunians, Talin, additional, Giri, Mamta, additional, Haberman, Yael, additional, Karns, Rebekah, additional, Prince, Jarod, additional, Arafat, Dalia, additional, Hsu, Nai-Yun, additional, Chuang, Ling-Shiang, additional, Argmann, Carmen, additional, Kasarskis, Andrew, additional, Suarez-Farinas, Mayte, additional, Gotman, Nathan, additional, Mengesha, Emebet, additional, Venkateswaran, Suresh, additional, Rufo, Paul A., additional, Baker, Susan S., additional, Sauer, Cary G., additional, Markowitz, James, additional, Pfefferkorn, Marian D., additional, Rosh, Joel R., additional, Boyle, Brendan M., additional, Mack, David R., additional, Baldassano, Robert N., additional, Shah, Sapana, additional, LeLeiko, Neal S., additional, Heyman, Melvin B., additional, Griffiths, Anne M., additional, Patel, Ashish S., additional, Noe, Joshua D., additional, Thomas, Sonia Davis, additional, Aronow, Bruce J., additional, Walters, Thomas D., additional, McGovern, Dermot P. B., additional, Hyams, Jeffrey S., additional, Kugathasan, Subra, additional, Cho, Judy H., additional, Denson, Lee A., additional, and Gibson, Greg, additional
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- 2021
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20. Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort
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Gettler, Kyle, primary, Levantovsky, Rachel, additional, Moscati, Arden, additional, Giri, Mamta, additional, Wu, Yiming, additional, Hsu, Nai-Yun, additional, Chuang, Ling-Shiang, additional, Sazonovs, Aleksejs, additional, Venkateswaran, Suresh, additional, Korie, Ujunwa, additional, Chasteau, Colleen, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Snapper, Scott B., additional, Daly, Mark J., additional, McGovern, Dermot P., additional, Brant, Steven R., additional, Rioux, John D., additional, Kugathasan, Subra, additional, Anderson, Carl A., additional, Itan, Yuval, additional, and Cho, Judy H., additional
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- 2021
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21. Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice
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Ziemba, Michael, primary, Barkhouse, Molly, additional, Uaesoontrachoon, Kitipong, additional, Giri, Mamta, additional, Hathout, Yetrib, additional, Dang, Utkarsh J., additional, Gordish-Dressman, Heather, additional, Nagaraju, Kanneboyina, additional, and Hoffman, Eric P., additional
- Published
- 2021
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22. Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
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Hathazi, Denisa, primary, Griffin, Helen, additional, Jennings, Matthew J, additional, Giunta, Michele, additional, Powell, Christopher, additional, Pearce, Sarah F, additional, Munro, Benjamin, additional, Wei, Wei, additional, Boczonadi, Veronika, additional, Poulton, Joanna, additional, Pyle, Angela, additional, Calabrese, Claudia, additional, Gomez‐Duran, Aurora, additional, Schara, Ulrike, additional, Pitceathly, Robert D S, additional, Hanna, Michael G, additional, Joost, Kairit, additional, Cotta, Ana, additional, Paim, Julia Filardi, additional, Navarro, Monica Machado, additional, Duff, Jennifer, additional, Mattman, Andre, additional, Chapman, Kristine, additional, Servidei, Serenella, additional, Della Marina, Adela, additional, Uusimaa, Johanna, additional, Roos, Andreas, additional, Mootha, Vamsi, additional, Hirano, Michio, additional, Tulinius, Mar, additional, Giri, Mamta, additional, Hoffmann, Eric P, additional, Lochmüller, Hanns, additional, DiMauro, Salvatore, additional, Minczuk, Michal, additional, Chinnery, Patrick F, additional, Müller, Juliane S, additional, and Horvath, Rita, additional
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- 2020
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23. Identifying novel high-impact rare disease-causing mutations, genes and pathways in exomes of Ashkenazi Jewish inflammatory bowel disease patients
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Wu, Yiming, primary, Gettler, Kyle, additional, Giri, Mamta, additional, Li, Dalin, additional, Bayrak, Cigdem Sevim, additional, Jain, Aayushee, additional, Maffucci, Patrick, additional, Sabic, Ksenija, additional, Vleck, Tielman Van, additional, Nadkarni, Girish, additional, Denson, Lee A., additional, Ostrer, Harry, additional, Kugathasan, Subra, additional, Stenson, Peter D., additional, Cooper, David N., additional, Schumm, L. Philip, additional, Snapper, Scott, additional, Daly, Mark J., additional, Haritunians, Talin, additional, Duerr, Richard H., additional, Silverberg, Mark S., additional, Rioux, John D., additional, Brant, Steven R., additional, McGovern, Dermot, additional, Cho, Judy H., additional, and Itan, Yuval, additional
- Published
- 2020
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24. Mo1112 IDENTIFYING NOVEL HIGH-IMPACT RARE DISEASE-CAUSING MUTATIONS, GENES AND PATHWAYS IN EXOMES OF ASHKENAZI JEWISH INFLAMMATORY BOWEL DISEASE PATIENTS
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wu, yiming, primary, Jain, Aayushee, additional, Sevim, Cigdem, additional, Li, Dalin, additional, giri, mamta, additional, Gettler, Kyle, additional, Mengesha, Emebet, additional, Schumm, L. Philip, additional, Haritunians, Talin, additional, McGovern, Dermot P.B., additional, Cho, Judy H., additional, and Itan, Yuval, additional
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- 2020
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25. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy
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Martin, Jerome C., primary, Chang, Christie, additional, Boschetti, Gilles, additional, Ungaro, Ryan, additional, Giri, Mamta, additional, Grout, John A., additional, Gettler, Kyle, additional, Chuang, Ling-shiang, additional, Nayar, Shikha, additional, Greenstein, Alexander J., additional, Dubinsky, Marla, additional, Walker, Laura, additional, Leader, Andrew, additional, Fine, Jay S., additional, Whitehurst, Charles E., additional, Mbow, M Lamine, additional, Kugathasan, Subra, additional, Denson, Lee A., additional, Hyams, Jeffrey S., additional, Friedman, Joshua R., additional, Desai, Prerak T., additional, Ko, Huaibin M., additional, Laface, Ilaria, additional, Akturk, Guray, additional, Schadt, Eric E., additional, Salmon, Helene, additional, Gnjatic, Sacha, additional, Rahman, Adeeb H., additional, Merad, Miriam, additional, Cho, Judy H., additional, and Kenigsberg, Ephraim, additional
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- 2019
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26. Zebrafish modeling of intestinal injury, bacterial exposures and medications defines epithelial in vivo responses relevant to human inflammatory bowel disease
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Chuang, Ling-shiang, primary, Morrison, Joshua, additional, Hsu, Nai-yun, additional, Labrias, Philippe Ronel, additional, Nayar, Shikha, additional, Chen, Ernie, additional, Villaverde, Nicole, additional, Facey, Jody Ann, additional, Boschetti, Gilles, additional, Giri, Mamta, additional, Castillo-Martin, Mireia, additional, Thin, Tin Htwe, additional, Sharma, Yashoda, additional, Chu, Jaime, additional, and Cho, Judy H., additional
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- 2019
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27. Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets: Crohn’s disease gene prioritization
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Gettler, Kyle, Giri, Mamta, Kenigsberg, Ephraim, Martin, Jerome, Chuang, Ling-Shiang, Hsu, Nai-Yun, Denson, Lee A., Hyams, Jeffrey S., Griffiths, Anne, Noe, Joshua D., Crandall, Wallace V., Mack, David R., Kellermayer, Richard, Abraham, Clara, Hoffman, Gabriel, Kugathasan, Subra, and Cho, Judy H.
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Male ,Adolescent ,Quantitative Trait Loci ,Sequence Analysis, DNA ,Polymorphism, Single Nucleotide ,Article ,Monocytes ,Crohn Disease ,Case-Control Studies ,Child, Preschool ,Humans ,Female ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Child ,Transcriptome ,Algorithms ,Software ,Genome-Wide Association Study - Abstract
Genome-wide association studies have identified approximately 170 loci associated with Crohn’s disease (CD), and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD-locus genes are most likely to be disease-related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly-diagnosed, untreated CD patients and controls and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying forty genome-wide significant genes. Co-expression network analysis identified a single gene module which was substantially enriched for CD-locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared to non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.
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- 2019
28. Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets
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Gettler, Kyle, primary, Giri, Mamta, additional, Kenigsberg, Ephraim, additional, Martin, Jerome, additional, Chuang, Ling-Shiang, additional, Hsu, Nai-Yun, additional, Denson, Lee A., additional, Hyams, Jeffrey S., additional, Griffiths, Anne, additional, Noe, Joshua D., additional, Crandall, Wallace V., additional, Mack, David R., additional, Kellermayer, Richard, additional, Abraham, Clara, additional, Hoffman, Gabriel, additional, Kugathasan, Subra, additional, and Cho, Judy H., additional
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- 2019
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29. PDPR Gene Expression Correlates with Exercise-Training Insulin Sensitivity Changes
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Barberio, Matthew D., Huffman, Kim M., Giri, Mamta, Hoffman, Eric P., Kraus, William E., and Hubal, Monica J.
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Male ,Gene Expression ,Middle Aged ,Article ,Pyruvate Dehydrogenase (Lipoamide)-Phosphatase ,Cardiovascular Diseases ,Risk Factors ,Humans ,Female ,Calcium Signaling ,Longitudinal Studies ,Obesity ,Insulin Resistance ,Sedentary Behavior ,Muscle, Skeletal ,Exercise - Abstract
Whole body insulin sensitivity (Si) typically improves after aerobic exercise training; however, individual responses can be highly variable. The purpose of this study was to use global gene expression to identify skeletal muscle genes that correlate with exercise-induced Si changes.Longitudinal cohorts from the Studies of Targeted Risk Reduction Intervention through Defined Exercise were used as Discovery (Affymetrix) and Confirmation (Illumina) of vastus lateralis gene expression profiles. Discovery (n = 39; 21 men) and Confirmation (n = 42; 19 men) cohorts were matched for age (52 ± 8 vs 51 ± 10 yr), body mass index (30.4 ± 2.8 vs 29.7 ± 2.8 kg·m), and V˙O2max (30.4 ± 2.8 vs 29.7 ± 2.8 mL·kg·min). Si was determined via intravenous glucose tolerance test pretraining and posttraining. Pearson product-moment correlation coefficients determined relationships between a) baseline and b) training-induced changes in gene expression and %ΔSi after training.Expression of 2454 (Discovery) and 1778 genes (Confirmation) at baseline were significantly (P0.05) correlated to %ΔSi; 112 genes overlapped. Pathway analyses identified Ca signaling-related transcripts in this 112-gene list. Expression changes of 1384 (Discovery) and 1288 genes (Confirmation) after training were significantly (P0.05) correlated to %ΔSi; 33 genes overlapped, representing contractile apparatus of skeletal and smooth muscle genes. Pyruvate dehydrogenase phosphatase regulatory subunit expression at baseline (P = 0.01, r = 0.41) and posttraining (P = 0.01, r = 0.43) were both correlated with %ΔSi.Exercise-induced adaptations in skeletal muscle Si are related to baseline levels of Ca-regulating transcripts, which may prime the muscle for adaptation. Relationships between %ΔSi and pyruvate dehydrogenase phosphatase regulatory, a regulatory subunit of the pyruvate dehydrogenase complex, indicate that the Si response is strongly related to key steps in metabolic regulation.
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- 2016
30. Association Study of Exon Variants in the NF-kappa B and TGF beta Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy
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Bello, Luca, Punetha, Jaya, Gordish Dressman, Heather, Giri, Mamta, Hoffman, Eric P, Barp, Andrea, Vianello, Sara, Pegoraro, Elena, Flanigan, Kevin M., Weiss, Robert B., Spitali, Pietro, Aartsma Rus, Annemieke, Straub, Volker, Lochmüller, Hanns, Muntoni, Francesco, Zaharieva, Irina, Ferlini, Alessandra, Mercuri, Eugenio Maria, Tuffery Giraud, Sylvie, Claustres, Mireille, Mcdonald, Craig M., Dunn, Diane M., Swoboda, Kathryn J., Gappmaier, Eduard, Howard, Michael T., Sampson, Jacinda B., Bromberg, Mark B., Butterfield, Russell, Kerr, Lynne, Pestronk, Alan, Florence, Julaine M., Connolly, Anne, Lopate, Glenn, Golumbek, Paul, Schierbecker, Jeanine, Malkus, Betsy, Renna, Renee, Siener, Catherine, Finkel, Richard S., Bonnemann, Carsten G., Medne, Livija, Glanzman, Allan M., Flickinger, Jean, Mendell, Jerry R., King, Wendy M., Lowes, Linda, Alfano, Lindsay, Mathews, Katherine D., Stephan, Carrie, Laubenthal, Karla, Baldwin, Kris, Wong, Brenda, Morehart, Paula, Meyer, Amy, Day, John W., Naughton, Cameron E., Margolis, Marcia, Cnaan, Avital, Abresch, Richard T., Henricson, Erik K., Morgenroth, Lauren P., Duong, Tina, Chidambaranathan, V. Viswanathan, Biggar, W. Douglas, Mcadam, Laura C., Mah, Jean, Tulinius, Mar, Leshner, Robert, Rocha, Carolina Tesi, Thangarajh, Mathula, Kornberg, Andrew, Ryan, Monique, Nevo, Yoram, Dubrovsky, Alberto, Clemens, Paula R., Abdel Hamid, Hoda, Connolly, Anne M., Teasley, Jean, Bertorini, Tulio E., North, Kathryn, Webster, Richard, Kolski, Hanna, Kuntz, Nancy, Driscoll, Sherilyn, Carlo, Jose, Gorni, Ksenija, Lotze, Timothy, Karachunski, Peter, Bodensteiner, John B., Universita degli Studi di Padova, Department of Pediatric Nephrology, Maria Fareri Children's Hospital, Valhalla, New York, New York Medical College (NYMC), Human Genetics, Great Ormond Street Hospital for Children [London] (GOSH), Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, Università degli Studi di Ferrara (UniFE), Università cattolica del Sacro Cuore [Milano] (Unicatt), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Neurology, Newcastle University [Newcastle], Department of Neurosciences [Padova, Italy], University of Padova [Padova, Italy], Massachusetts General Hospital [Boston], King‘s College London, Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Child Development & Exercise Center, Royal Children's Hospital, Washington University in Saint Louis (WUSTL), Institute for Neuromuscular Research, The University of Sydney, Rothamsted Research, University of Alberta, Department of Pediatrics, Feinberg School of Medicine, Northwestern University [Evanston]-Northwestern University [Evanston]-Northwestern University, Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
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0301 basic medicine ,Candidate gene ,Genetics ,Genetics (clinical) ,Duchenne muscular dystrophy ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Dystrophin ,0302 clinical medicine ,Transforming Growth Factor beta ,Osteopontin ,Muscular Dystrophy ,Muscular dystrophy ,Modifier ,Child ,Exome ,biology ,NF-kappa B ,Exons ,Single Nucleotide ,Adolescent ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,White People ,NO ,03 medical and health sciences ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,Report ,medicine ,Humans ,CD40 Antigens ,Polymorphism ,Glucocorticoids ,Alleles ,Case-Control Studies ,Genes, Modifier ,Genome-Wide Association Study ,Latent TGF-beta Binding Proteins ,Muscular Dystrophy, Duchenne ,Mutation ,medicine.disease ,Duchenne ,030104 developmental biology ,Genes ,biology.protein ,030217 neurology & neurosurgery - Abstract
International audience; The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.
- Published
- 2016
31. Abstract 3338: BP1 induces an epithelial to mesenchymal transition in breast cancer cells by modulating the Twist/IL6 pathway
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Vesuna, Farhad, primary, Hwang, Bin-Jin, additional, Rheey, Jinguen, additional, Giri, Mamta, additional, Gill, Mandeep, additional, Fu, Sidney W., additional, Irving, Ashley, additional, Lisok, Ala, additional, Bergman, Yehudit, additional, Raman, Venu, additional, and Berg, Patricia E., additional
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- 2018
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32. miRTarVis+: Web-based interactive visual analytics tool for microRNA target predictions
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L'Yi, Sehi, primary, Jung, Daekyoung, additional, Oh, Minsik, additional, Kim, Bohyoung, additional, Freishtat, Robert J., additional, Giri, Mamta, additional, Hoffman, Eric, additional, and Seo, Jinwook, additional
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- 2017
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33. Airway Secretory microRNAome Changes during Rhinovirus Infection in Early Childhood
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Gutierrez, Maria J., primary, Gomez, Jose L., additional, Perez, Geovanny F., additional, Pancham, Krishna, additional, Val, Stephanie, additional, Pillai, Dinesh K., additional, Giri, Mamta, additional, Ferrante, Sarah, additional, Freishtat, Robert, additional, Rose, Mary C., additional, Preciado, Diego, additional, and Nino, Gustavo, additional
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- 2016
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34. HG-61MOLECULAR CHARACTERIZATION OFIN VIVOANDIN VITROMODELS OF DIPG
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Stampar, Mojca, primary, Saratsis, Amanda, additional, Brown, Kristy, additional, Yadavilli, Sridevi, additional, Raabe, Eric, additional, Warren, Kathy, additional, Kambhampati, Madhuri, additional, Giri, Mamta, additional, Gupta, Nalin, additional, Packer, Roger, additional, and Nazarian, Javad, additional
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- 2016
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35. Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases
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Punetha, Jaya, primary, Kesari, Akanchha, additional, Uapinyoying, Prech, additional, Giri, Mamta, additional, Clarke, Nigel F., additional, Waddell, Leigh B., additional, North, Kathryn N., additional, Ghaoui, Roula, additional, O’Grady, Gina L., additional, Oates, Emily C., additional, Sandaradura, Sarah A., additional, Bönnemann, Carsten G., additional, Donkervoort, Sandra, additional, Plotz, Paul H., additional, Smith, Edward C., additional, Tesi-Rocha, Carolina, additional, Bertorini, Tulio E., additional, Tarnopolsky, Mark A., additional, Reitter, Bernd, additional, Hausmanowa-Petrusewicz, Irena, additional, and Hoffman, Eric P., additional
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- 2016
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36. miRTarVis: an interactive visual analysis tool for microRNA-mRNA expression profile data
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Jung, Daekyoung, primary, Kim, Bohyoung, additional, Freishtat, Robert J, additional, Giri, Mamta, additional, Hoffman, Eric, additional, and Seo, Jinwook, additional
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- 2015
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37. Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity
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Rowlands, David S., primary, Page, Rachel A., additional, Sukala, William R., additional, Giri, Mamta, additional, Ghimbovschi, Svetlana D., additional, Hayat, Irum, additional, Cheema, Birinder S., additional, Lys, Isabelle, additional, Leikis, Murray, additional, Sheard, Phillip W., additional, Wakefield, St. John, additional, Breier, Bernhard, additional, Hathout, Yetrib, additional, Brown, Kristy, additional, Marathi, Ramya, additional, Orkunoglu-Suer, Funda E., additional, Devaney, Joseph M., additional, Leiken, Benjamin, additional, Many, Gina, additional, Krebs, Jeremy, additional, Hopkins, Will G., additional, and Hoffman, Eric P., additional
- Published
- 2014
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38. Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy
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Dadgar, Sherry, primary, Wang, Zuyi, additional, Johnston, Helen, additional, Kesari, Akanchha, additional, Nagaraju, Kanneboyina, additional, Chen, Yi-Wen, additional, Hill, D. Ashley, additional, Partridge, Terence A., additional, Giri, Mamta, additional, Freishtat, Robert J., additional, Nazarian, Javad, additional, Xuan, Jianhua, additional, Wang, Yue, additional, and Hoffman, Eric P., additional
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- 2014
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39. miRTarVis: an interactive visual analysis tool for microRNA-mRNA expression profile data.
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Daekyoung Jung, Bohyoung Kim, Freishtat, Robert J., Giri, Mamta, Hoffman, Eric, and Seo, Jinwook
- Subjects
GENE expression ,MICRORNA ,MOLECULAR biology ,NUCLEOTIDES ,ALGORITHMS - Abstract
Background: MicroRNAs (miRNA) are short nucleotides that down-regulate its target genes. Various miRNA target prediction algorithms have used sequence complementarity between miRNA and its targets. Recently, other algorithms tried to improve sequence-based miRNA target prediction by exploiting miRNA-mRNA expression profile data. Some web-based tools are also introduced to help researchers predict targets of miRNAs from miRNA-mRNA expression profile data. A demand for a miRNA-mRNA visual analysis tool that features novel miRNA prediction algorithms and more interactive visualization techniques exists. Results: We designed and implemented miRTarVis, which is an interactive visual analysis tool that predicts targets of miRNAs from miRNA-mRNA expression profile data and visualizes the resulting miRNA-target interaction network. miRTarVis has intuitive interface design in accordance with the analysis procedure of load, filter, predict, and visualize. It predicts targets of miRNA by adopting Bayesian inference and MINE analyses, as well as conventional correlation and mutual information analyses. It visualizes a resulting miRNA-mRNA network in an interactive Treemap, as well as a conventional node-link diagram. miRTarVis is available at http://hcil.snu.ac.kr/~rati/ miRTarVis/index.html. Conclusions: We reported findings from miRNA-mRNA expression profile data of asthma patients using miRTarVis in a case study. miRTarVis helps to predict and understand targets of miRNA from miRNA-mRNA expression profile data. [ABSTRACT FROM AUTHOR]
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- 2015
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40. Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
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Hathazi, Denisa, Griffin, Helen, Jennings, Matthew J, Giunta, Michele, Powell, Christopher, Pearce, Sarah F, Munro, Benjamin, Wei, Wei, Boczonadi, Veronika, Poulton, Joanna, Pyle, Angela, Calabrese, Claudia, Gomez-Duran, Aurora, Schara, Ulrike, Pitceathly, Robert DS, Hanna, Michael G, Joost, Kairit, Cotta, Ana, Paim, Julia Filardi, Navarro, Monica Machado, Duff, Jennifer, Mattman, Andre, Chapman, Kristine, Servidei, Serenella, Della Marina, Adela, Uusimaa, Johanna, Roos, Andreas, Mootha, Vamsi, Hirano, Michio, Tulinius, Mar, Giri, Mamta, Hoffmann, Eric P, Lochmüller, Hanns, DiMauro, Salvatore, Minczuk, Michal, Chinnery, Patrick F, Müller, Juliane S, and Horvath, Rita
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Male ,Proteomics ,tRNA Methyltransferases ,reversible infantile respiratory chain deficiency ,Mitochondrial Diseases ,Adolescent ,mitochondrial myopathy ,Gene Expression ,Infant ,Mitochondrial Myopathies ,digenic inheritance ,DNA, Mitochondrial ,3. Good health ,Cell Line ,Mitochondria ,Pedigree ,Quadriceps Muscle ,Mitochondrial Proteins ,homoplasmic tRNA mutation ,Mutation ,Humans ,Female - Abstract
Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
41. A Role for CXCR3 Ligands as Biomarkers of Post-Operative Crohn's Disease Recurrence.
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Walshe M, Nayeri S, Ji J, Hernandez-Rocha C, Sabic K, Hu L, Giri M, Nayar S, Brant S, McGovern DPB, Rioux JD, Duerr RH, Cho JH, Schumm PL, Lazarev M, and Silverberg MS
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- Bayes Theorem, Biomarkers metabolism, Colonoscopy, Humans, Ileum pathology, Receptors, CXCR3, Recurrence, Retrospective Studies, Crohn Disease diagnosis, Crohn Disease metabolism, Crohn Disease surgery
- Abstract
Background and Aims: Crohn's disease [CD] recurrence following ileocolic resection [ICR] is common. We sought to identify blood-based biomarkers associated with CD recurrence., Methods: CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins [Olink Proteomics]. Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were used in receiver operating characteristic [ROC] analysis to examine the ability to identify CD recurrence [Rutgeerts score ≥i2]. Existing single cell data were interrogated to further elucidate the role of the identified proteins., Results: Data from 276 colonoscopies in 213 patients were available. Median time from surgery to first and second colonoscopy was 7 (interquartile range [IQR] 6-9) and 19 [IQR 16-23] months, respectively. Disease recurrence was evident at 60 [30%] first and 36 [49%] second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-tumour necrosis factor drugs, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone: area under the curve [AUC] 0.75 (95% confidence interval [CI]: 0.66-0.82] vs 0.64 [95% CI 0.56-0.72], p = 0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of the identified proteins., Conclusions: CXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid in identification of CD recurrence., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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