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502 results on '"Kugathasan S"'

4. P115 Ustekinumab in DEVELOP: A safety analysis from an Inflammatory Bowel Disease multicenter, prospective, long-term registry of paediatric patients

Author

Koletzko, S, primary, Veereman, G, additional, Hyams, J, additional, Dubinsky, M, additional, Godwin, B, additional, Busse, C, additional, Strauss, R, additional, Volger, S, additional, Wang, Y, additional, Griffiths, A, additional, Colletti, R B, additional, Kugathasan, S, additional, Markowitz, J, additional, Winter, H S, additional, Escher, J, additional, Baldassano, R N, additional, Ruemmele, F, additional, Faubion, W, additional, and Gold, B, additional

Published
2024
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5. 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

8. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, A., Stevens, C.R., Venkataraman, G.R., Yuan, K., Avila, B., Abreu, M.T., Ahmad, T., Allez, M., Ananthakrishnan, A.N., Atzmon, G., Baras, A., Barrett, J.C., Barzilai, N., Beaugerie, L., Beecham, A., Bernstein, C.N., Bitton, A., Bokemeyer, B., Chan, A., Chung, D., Cleynen, I., Cosnes, J., Cutler, D.J., Daly, A., Damas, O.M., Datta, L.W., Dawany, N., Devoto, M., Dodge, S., Ellinghaus, E., Fachal, L., Farkkila, M., Faubion, W., Ferreira, M., Franchimont, D., Gabriel, S.B., Ge, T., Georges, M., Gettler, K., Giri, M., Glaser, B., Goerg, S., Goyette, P., Graham, D., Hamalainen, E., Haritunians, T., Heap, G.A., Hiltunen, M., Hoeppner, M., Horowitz, J.E., Irving, P., Iyer, V., Jalas, C., Kelsen, J., Khalili, H., Kirschner, B.S., Kontula, K., Koskela, J.T., Kugathasan, S., Kupcinskas, J., Lamb, C.A., Laudes, M., Levesque, C., Levine, A.P., Lewis, J.D., Liefferinckx, C., Loescher, B.S., Louis, E., Mansfield, J., May, S., McCauley, J.L., Mengesha, E., Mni, M., Moayyedi, P., Moran, C.J., Newberry, R.D., O'Charoen, S., Okou, D.T., Oldenburg, B., Ostrer, H., Palotie, A., Paquette, J., Pekow, J., Peter, I., Pierik, M.J., Ponsioen, C.Y., Pontikos, N., Prescott, N., Pulver, A.E., Rahmouni, S., Rice, D.L., Saavalainen, P., Sands, B., Sartor, R.B., Schiff, E.R., Schreiber, S., Schumm, L.P., Segal, A.W., Seksik, P., Shawky, R., Sheikh, S.Z., Silverberg, M.S., Simmons, A., Skeiceviciene, J., Sokol, H., Solomonson, M., Somineni, H., Sun, D., Targan, S., Turner, D., Uhlig, H.H., Meulen, A.E. van der, Vermeire, S., Verstockt, S., Voskuil, M.D., Winter, H.S., Young, J., Duerr, R.H., Franke, A., Brant, S.R., Cho, J., Weersma, R.K., Parkes, M., Xavier, R.J., Rivas, M.A., Rioux, J.D., McGovern, D.P.B., Huang, H.L., Anderson, C.A., Daly, M.J., Belgium IBD Consortium, Cedars-Sinai IBD, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, NIHR IBD BioResource, Regeneron Genetics Center, SHARE Consortium, SPARC IBD Network, UK IBD Genetics Consortium, Interne Geneeskunde, MUMC+: MA Maag Darm Lever (9), RS: NUTRIM - R2 - Liver and digestive health, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Crohn Disease, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Published
2022

9. P711 Stool microbiome communities predict remission in pediatric Crohn’s disease patients even after start of treatment

Author

Verburgt, C, primary, Dunn, K A, additional, Bielawski, J P, additional, Otley, A R, additional, Heyman, M B, additional, Sunseri, W, additional, Shouval, D, additional, Levine, A, additional, de Meij, T, additional, Hyams, J S, additional, Denson, L A, additional, Kugathasan, S, additional, Benninga, M A, additional, de Jonge, W J, additional, and Van Limbergen, J E, additional

Published
2022
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10. P089 Long ncRNA Landscape in the Rectum of Treatment Naïve Early Onset Ulcerative Colitis Highlights Association with Severity and Early and Late Disease Outcome, with Potential Role in Epithelial Metabolic Functions

Author

Haberman Ziv, Y, primary, Braun, T, additional, Sosnovski, K, additional, Amir, A, additional, VanDussen, K, additional, Igor Ulitsky, I U, additional, Griffiths, A, additional, Walters, T, additional, Mack, D, additional, Boyle, B, additional, Kugathasan, S, additional, Jegga, A, additional, Hyams, J, additional, and Denson, L, additional

Published
2022
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11. Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations

Author

Degenhardt, F, Mayr, G, Wendorff, M, Boucher, G, Ellinghaus, E, Ellinghaus, D, ElAbd, H, Rosati, E, Huebenthal, M, Juzenas, S, Abedian, S, Vahedi, H, Thelma, BK, Yang, S-K, Ye, BD, Cheon, JH, Datta, LW, Daryani, NE, Ellul, P, Esaki, M, Fuyuno, Y, McGovern, DPB, Haritunians, T, Hong, M, Juyal, G, Jung, ES, Kubo, M, Kugathasan, S, Lenz, TL, Leslie, S, Malekzadeh, R, Midha, V, Motyer, A, Ng, SC, Okou, DT, Raychaudhuri, S, Schembri, J, Schreiber, S, Song, K, Sood, A, Takahashi, A, Torres, EA, Umeno, J, Alizadeh, BZ, Weersma, RK, Wong, SH, Yamazaki, K, Karlsen, TH, Rioux, JD, Brant, SR, Franke, A, Degenhardt, F, Mayr, G, Wendorff, M, Boucher, G, Ellinghaus, E, Ellinghaus, D, ElAbd, H, Rosati, E, Huebenthal, M, Juzenas, S, Abedian, S, Vahedi, H, Thelma, BK, Yang, S-K, Ye, BD, Cheon, JH, Datta, LW, Daryani, NE, Ellul, P, Esaki, M, Fuyuno, Y, McGovern, DPB, Haritunians, T, Hong, M, Juyal, G, Jung, ES, Kubo, M, Kugathasan, S, Lenz, TL, Leslie, S, Malekzadeh, R, Midha, V, Motyer, A, Ng, SC, Okou, DT, Raychaudhuri, S, Schembri, J, Schreiber, S, Song, K, Sood, A, Takahashi, A, Torres, EA, Umeno, J, Alizadeh, BZ, Weersma, RK, Wong, SH, Yamazaki, K, Karlsen, TH, Rioux, JD, Brant, SR, and Franke, A

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Published
2021

12. OP32 Stool microbiome communities predict remission in treatment-naïve Pediatric Crohn’s Disease patients

Author

Verburgt, C, primary, Dunn, K, additional, Bielawski, J, additional, Otley, A, additional, Heyman, M, additional, Sunseri, W, additional, Shouval, D, additional, Levine, A, additional, de Meij, T, additional, Hyams, J, additional, Denson, L, additional, Kugathasan, S, additional, Benninga, M, additional, de Jonge, W, additional, and Van Limbergen, J, additional

Published
2021
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13. Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease

Author

Kugathasan, S., Saubermann, L.J., Smith, L., Kou, D., Itoh, J., Binion, D.G., Levine, A.D., Blumberg, R.S., and Fiocchi, C.

Subjects
Crohn's disease -- Development and progression, Crohn's disease -- Physiological aspects, Crohn's disease -- Research, T cells -- Physiological aspects, T cells -- Research, Immune response -- Regulation, Immune response -- Research, Health
Published
2007

14. DOP89 Pre-treatment mucosal inflammatory and wound healing gene programmes reveal mechanisms associated with future stricturing behaviour during 5-year follow-up in paediatric Crohn’s disease

Author

Haberman Ziv, Y, primary, Minar, P, additional, Karns, R, additional, Dexheimer, P, additional, Ghandikota, S, additional, Tegge, S, additional, Shapiro, D, additional, Shuler, B, additional, Venkateswaran, S, additional, Braun, T, additional, Aronow, B, additional, Gibson, G, additional, Hyams, J, additional, Kugathasan, S, additional, Jegga, A, additional, and Denson, L, additional

Published
2020
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15. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

16. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, 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, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, 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, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, 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, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, Zhao, ZZ, Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, A, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, Mj, vander Meulen-de Jong, Ae, van der Woude, Cj, Visschedijk, Mc, Lathrop, M, Hugot, Jp, Weersma, Rk, De Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, Jp, Ahmad, T, 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, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Buning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, Denapiene, G, Denson, La, Devaney, Kl, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, 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, Xh, Huang, Hl, 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, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dpb, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sme, Nikolaus, S, Ning, K, Nothen, 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, Schulte, D, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, M, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, Ah, Stempak, Jm, Stronati, L, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, Hy, Zhao, Zz, Gastroenterology & Hepatology, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, and UCL - (MGD) Service de gastro-entérologie

Subjects
Adult, Male, Multifactorial Inheritance, QUANTITATIVE TRAIT LOCUS, Genotype, SEQUENCING DATA, Quantitative Trait Loci, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, Article, Cohort Studies, CODING VARIANTS, Crohn Disease, 80 and over, Journal Article, Medicine and Health Sciences, LOCUS, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Genetic Association Studies, Aged, Aged, 80 and over, Science & Technology, Female, Gene Expression Profiling, Inflammatory Bowel Diseases, Middle Aged, Sequence Analysis, DNA, COMPLEX TRAITS, Biology and Life Sciences, Single Nucleotide, DNA, CROHNS-DISEASE, Multidisciplinary Sciences, QUANTITATIVE TRAIT, RARE VARIANTS, Science & Technology - Other Topics, LOW-FREQUENCY, Sequence Analysis, INFLAMMATORY-BOWEL-DISEASE
Abstract

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach., Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.

Published
2018

20. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease

Author

Denson, LA, Jurickova, I, Karns, R, Shaw, KA, Cutler, DJ, Okou, D, Alexander Valencia, C, Dodd, A, Mondal, K, Aronow, BJ, Haberman, Y, Linn, A, Price, A, Bezold, R, Lake, K, Jackson, K, Walters, TD, Griffiths, A, Baldassano, RN, Noe, JD, Hyams, JS, Crandall, WV, Kirschner, BS, Heyman, MB, Snapper, S, Guthery, SL, Dubinsky, MC, Leleiko, NS, Otley, AR, Xavier, RJ, Stevens, C, Daly, MJ, Zwick, ME, and Kugathasan, S

Subjects
Adult, Male, Adolescent, Neutrophils, Clinical Sciences, Crohn's Disease, Autoimmune Disease, Cytokine Receptor Common beta Subunit, Young Adult, Crohn Disease, Clinical Research, Receptors, Genetics, pediatric inflammatory bowel disease, Humans, 2.1 Biological and endogenous factors, whole-exome sequencing, Aetiology, Child, Preschool, STAT5, Gastroenterology & Hepatology, Inflammatory Bowel Disease, Granulocyte-Macrophage Colony-Stimulating Factor, Infant, neutrophil, GM-CSF, RNA sequencing, Prognosis, Case-Control Studies, Mutation, Female, Missense, Transcriptome, Digestive Diseases, Follow-Up Studies
Abstract

BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

Published
2019

21. Pediatric inflammatory bowel disease clinical innovations meeting of the Crohn's and colitis foundation: Charting the future of pediatric IBD

Author

Heller, C.A., Park, K.T., Mulberg, A., Bousvaros, A., Grossman, A.B., Kugathasan, S., Lee, D., Otley, A., Denson, L.A., Picoraro, J.A., Hyams, J.S., Ziring, D., Rosh, J.R., Weaver, A., Conklin, L.S., and Kappelman, M.D.

Subjects
digestive system diseases
Abstract

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure.

Published
2019
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22. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y., Dmitrieva, J., Theatre, E., Deffontaine, V., Rahmouni, S., Charloteaux, B., Crins, F., Docampo, E., Elansary, M., Gori, A.S., Lecut, C., Mariman, R., Mni, M., Oury, C., Altukhov, I., Alexeev, D., Aulchenko, Y., Amininejad, L., Bouma, G., Hoentjen, F., Lowenberg, M., Oldenburg, B., Pierik, M.J., vander Meulen-de Jong, A.E., Woude, C.J. van der, Visschedijk, M.C., Lathrop, M., Hugot, J.P., Weersma, R.K., Vos, M. de, Franchimont, D., Vermeire, S., Kubo, M., Louis, E., Georges, M., Abraham, C., Achkar, J.P., Ahmad, T., Ananthakrishnan, A.N., Andersen, V., Anderson, C.A., Andrews, J.M., Annese, V., Aumais, G., Baidoo, L., Baldassano, R.N., Bampton, P.A., Barclay, M., Barrett, J.C., Bayless, T.M., Bethge, J., Bitton, A., Boucher, G., Brand, S., Brandt, B., Brant, S.R., Buning, C., Chew, A., Cho, J.H., Cleynen, I., Cohain, A., Croft, A., Daly, M.J., D'Amato, M., Danese, S., Jong, D. de, Denapiene, G., Denson, L.A., Devaney, K.L., Dewit, O., D'Inca, R., Dubinsky, M., Duerr, R.H., Edwards, C., Ellinghaus, D., Essers, J., Ferguson, L.R., Festen, E.A., Fleshner, P., Florin, T., Franke, A., Fransen, K., Gearry, R., Gieger, C., Glas, J., Goyette, P., Green, T., Griffiths, A.M., Guthery, S.L., Hakonarson, H., Halfvarson, J., Hanigan, K., Haritunians, T., Hart, A., Hawkey, C., Hayward, N.K., Hedl, M., Henderson, P., Hu, X.H., Huang, H.L., Hui, K.Y., Imielinski, M., Ippoliti, A., Jonaitis, L., Jostins, L., Karlsen, T.H., Kennedy, N.A., Khan, M.A., Kiudelis, G., Krishnaprasad, K., Kugathasan, S., Kupcinskas, L., Latiano, A., Laukens, D., Lawrance, I.C., Lee, J.C., Lees, C.W., Leja, M., Limbergen, J. van, Lionetti, P., Liu, J.Z., Mahy, G., Mansfield, J., Massey, D., Mathew, C.G., McGovern, D.P.B., Milgrom, R., Mitrovic, M., Montgomery, G.W., Mowat, C., Newman, W., Ng, A., Ng, S.C., Ng, S.M.E., Nikolaus, S., Ning, K., Nothen, M., Oikonomou, I., Palmieri, O., Parkes, M., Phillips, A., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Proctor, D.D., Radford-Smith, G., Rahier, J.F., Raychaudhuri, S., Regueiro, M., Rieder, F., Rioux, J.D., Ripke, S., Roberts, R., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schadt, E.E., Schreiber, S., Schulte, D., Schumm, L.P., Scott, R., Seielstad, M., Sharma, Y., Silverberg, M.S., Simms, L.A., Skieceviciene, J., Spain, S.L., Steinhart, A.H., Stempak, J.M., Stronati, L., Sventoraityte, J., Targan, S.R., Taylor, K.M., Velde, A. ter, Torkvist, L., Tremelling, M., Sommeren, S. van, Vasiliauskas, E., Verspaget, H.W., Walters, T., Wang, K., Wang, M.H., Wei, Z., Whiteman, D., Wijmenga, C., Wilson, D.C., Winkelmann, J., Xavier, R.J., Zhang, B., Zhang, C.K., Zhang, H., Zhang, W., Zhao, H.Y., Zhao, Z.Z., and Int IBD Genetics Consortium

Published
2018

23. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, WGS500 Consortium, Oxford IBD cohort study investigators, COLORS in IBD group investigators, UK IBD Genetics Consortium, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, INTERVAL Study, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, D Pb, Cho, J, Powrie, F, Li, V Sw, Muise, AM, Uhlig, HH, Parkes, Miles [0000-0002-6467-0631], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Male, Genes, Modifier, Genome, Genotype, Colon, Mutation, Missense, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, digestive system diseases, Mice, Inbred C57BL, Mice, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Animals, Humans, Genetic Predisposition to Disease, Child, Reactive Oxygen Species, Genetic Association Studies
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
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24. IBD Serology and Disease Outcomes in African Americans with Crohn's Disease

Author

Kugathasan, S., Alexander, J.S., Baldassano, R.N., Sauer, C., Hofmekler, T., McGovern, D., Chopra, P., Hussain, S.Z., Bertha, M., Katz, J., Prince, J., Landers, C.J., Dubinsky, M.C., Patel, A., Bruce, B.B., Okou, D., Moulton, D.E., Osuntokun, B.O., Vasantharoopan, A., Kirschner, B.S., Wang, G., Kappelman, M.D., Saeed, S., Klapproth, J.-M.A., Cross, R.K., Dhere, T.A., and Kumar, A.

Abstract

Backgrounds: Recent studies have identified the role of serologic markers in characterizing disease phenotype, location, complications, and severity among Northern Europeans (NE) with Crohn's disease (CD). However, very little is known about the role of serology in CD among African Americans (AA). Our study explored the relationship between serology and disease phenotype in AA with CD, while controlling for genetic ancestry. Methods: AAs with CD were enrolled as participants through multicenter collaborative efforts. Serological levels of IgA anti-Saccharomyces cervisiae antibody (ASCA), IgG ASCA, E. coli outermembrane porin C, anti-CBir1, and ANCA were measured using enzyme-linked immunosorbent assays. Genotyping was performed using Illumina immunochip technology; an admixture rate was calculated for each subject. Multiple imputation by chained equations was performed to account for data missing at random. Logistic regression was used to calculate adjusted odds ratio (OR) for associations between serological markers and both complicated disease and disease requiring surgery. Results: A total of 358 patients were included in the analysis. The majority of our patients had inflammatory, noncomplicated disease (58.4%), perianal disease (55.7%), and documented colonic inflammation (86.8%). On multivariable analysis, both IgG ASCA and OmpC were associated with complicated disease (OR, 2.67; 95% CI, 1.67-4.28; OR, 2.23; 95% CI, 1.41-3.53, respectively) and disease requiring surgery (OR, 2.51; 95% CI, 1.49-4.22; OR, 3.57; 95% CI, 2.12-6.00). NE admixture to the African genome did not have any associations or interactions in relation to clinical outcome. Conclusions: Our study comprises the largest cohort of AAs with CD. The utility of serological markers for the prognosis of CD in NE applies equally to AA populations.

Published
2018
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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

Author

Martin, JC, primary, Boschetti, G, additional, Chang, C, additional, Ungaro, R, additional, Giri, M, additional, Chuang, LS, additional, Nayar, S, additional, Greenstein, A, additional, Dubinsky, M., additional, Walker, L, additional, Leader, A, additional, Fine, JS, additional, Whitehurst, CE, additional, Mbow, L, additional, Kugathasan, S, additional, Denson, L.A., additional, Hyams, J., additional, Friedman, JR, additional, Desai, P, additional, Ko, HM, additional, Laface, I, additional, Akturk, Guray, additional, Schadt, EE, additional, Gnjatic, S, additional, Rahman, A, additional, Merad, M, additional, Cho, JH, additional, and Kenigsberg, E, additional

Published
2018
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26. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), Zhao, Z.Z. (Zhen Z.), Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), and Zhao, Z.Z. (Zhen Z.)

Abstract

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Published
2018
Full Text
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27. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, R V, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, C G, Fiedler, K, McCarthy, D J, Sullivan, P B, Rodrigues, A, Travis, S P L, Moore, C, Sambrook, J, Ouwehand, W H, Roberts, D J, Danesh, J, Russell, R K, Wilson, D C, Kelsen, J R, Cornall, R, Denson, L A, Kugathasan, S, Knaus, U G, Serra, E G, Anderson, C A, Duerr, R H, McGovern, D Pb, Cho, J, Powrie, F, Li, V Sw, Muise, A M, Uhlig, H H, and Tomlinson, Ian

Subjects
Journal Article, digestive system diseases
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.Mucosal Immunology advance online publication 1 November 2017. doi:10.1038/mi.2017.74.

Published
2017

28. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, primary, Bryant, RV, additional, Pandey, S, additional, Capitani, M, additional, Meran, L, additional, Cazier, J-B, additional, Jung, J, additional, Mondal, K, additional, Parkes, M, additional, Mathew, CG, additional, Fiedler, K, additional, McCarthy, DJ, additional, Sullivan, PB, additional, Rodrigues, A, additional, Travis, SPL, additional, Moore, C, additional, Sambrook, J, additional, Ouwehand, WH, additional, Roberts, DJ, additional, Danesh, J, additional, Russell, RK, additional, Wilson, DC, additional, Kelsen, JR, additional, Cornall, R, additional, Denson, LA, additional, Kugathasan, S, additional, Knaus, UG, additional, Serra, EG, additional, Anderson, CA, additional, Duerr, RH, additional, McGovern, DPB, additional, Cho, J, additional, Powrie, F, additional, Li, VSW, additional, Muise, AM, additional, and Uhlig, HH, additional

Published
2018
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29. 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

30. 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

33. Genetic sharing and heritability of paediatric age of onset autoimmune diseases

Author

Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, Hakonarson, H, Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, and Hakonarson, H

Abstract

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Published
2015

34. 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

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

Author

Anderson, C.A. Boucher, G. Lees, C.W. Franke, A. D'Amato, M. Taylor, K.D. Lee, J.C. Goyette, P. Imielinski, M. Latiano, A. Lagacé, C. Scott, R. Amininejad, L. Bumpstead, S. Baidoo, L. Baldassano, R.N. Barclay, M. Bayless, T.M. Brand, S. Büning, C. Colombel, J.-F. Denson, L.A. De Vos, M. Dubinsky, M. Edwards, C. Ellinghaus, D. Fehrmann, R.S.N. Floyd, J.A.B. Florin, T. Franchimont, D. Franke, L. Georges, M. Glas, J. Glazer, N.L. Guthery, S.L. Haritunians, T. Hayward, N.K. Hugot, J.-P. Jobin, G. Laukens, D. Lawrance, I. Lémann, M. Levine, A. Libioulle, C. Louis, E. McGovern, D.P. Milla, M. Montgomery, G.W. Morley, K.I. Mowat, C. Ng, A. Newman, W. Ophoff, R.A. Papi, L. Palmieri, O. Peyrin-Biroulet, L. Panés, J. Phillips, A. Prescott, N.J. Proctor, D.D. Roberts, R. Russell, R. Rutgeerts, P. Sanderson, J. Sans, M. Schumm, P. Seibold, F. Sharma, Y. Simms, L.A. Seielstad, M. Steinhart, A.H. Targan, S.R. Van Den Berg, L.H. Vatn, M. Verspaget, H. Walters, T. Wijmenga, C. Wilson, D.C. Westra, H.-J. Xavier, R.J. Zhao, Z.Z. Ponsioen, C.Y. Andersen, V. Torkvist, L. Gazouli, M. Anagnou, N.P. Karlsen, T.H. Kupcinskas, L. Sventoraityte, J. Mansfield, J.C. Kugathasan, S. Silverberg, M.S. Halfvarson, J. Rotter, J.I. Mathew, C.G. Griffiths, A.M. Gearry, R. Ahmad, T. Brant, S.R. Chamaillard, M. Satsangi, J. Cho, J.H. Schreiber, S. Daly, M.J. Barrett, J.C. Parkes, M. Annese, V. Hakonarson, H. Radford-Smith, G. Duerr, R.H. Vermeire, S. Weersma, R.K. Rioux, J.D.

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. © 2011 Nature America, Inc. All rights reserved.

Published
2011

36. O-11: Real world outcomes of contemporary treatments in children with Crohn’s disease: observations from the pediatric IBD collaborative research group registry

Author

Markowitz, J., primary, Lerer, T., additional, Morganstern, J., additional, Deslandres, C., additional, Tomer, G., additional, Schaefer, M., additional, Kugathasan, S., additional, Faubion, W., additional, Kappelman, M., additional, Sudel, B., additional, Hitch, M., additional, Keljo, D., additional, Grossman, A., additional, Carvalho, R., additional, Leleiko, N., additional, Saeed, S., additional, Oliva-Hemker, M., additional, Kay, M., additional, Rosh, J., additional, Pfefferkorn, M., additional, Otley, A., additional, Rick, J., additional, Mack, D., additional, Cabrera, J., additional, Griffiths, A., additional, and Hyams, J., additional

Published
2014
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37. Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

Author

Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Regueiro, M, Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, and Regueiro, M

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.

Published
2013

38. NOX1loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, DPB, Cho, J, Powrie, F, Li, VSW, Muise, AM, and Uhlig, HH

Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivocolonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
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39. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Author

Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., et al., Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., Jong, D.J. de, Devaney, K.L., Dubinsky, M.C., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R.B., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C.J., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W.G., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., Vos, M de, Wijmenga, C., Winkelmann, J., Wilson, D.C., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., Silverberg, M.S., Annesse, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C., Cho, J.H., Donnelly, J.P., and et al.

Abstract

Item does not contain fulltext

Published
2012

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

Author

Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, Rioux, JD, Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, and Rioux, JD

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

42. Association of Linear Growth Impairment in Pediatric Crohn's Disease and a Known Height Locus: A Pilot Study

Author

Lee, J.J. (Jessica), Essers, J.B. (Jonah), Kugathasan, S. (Subra), Escher, J.C. (Johanna), Lettre, G. (Guillaume), Butler, J.L. (Johannah), Stephens, M.C. (Michael), Ramoni, M.F. (Marco), Grand, R.J. (Richard), Hirschhorn, J.N. (Joel), Lee, J.J. (Jessica), Essers, J.B. (Jonah), Kugathasan, S. (Subra), Escher, J.C. (Johanna), Lettre, G. (Guillaume), Butler, J.L. (Johannah), Stephens, M.C. (Michael), Ramoni, M.F. (Marco), Grand, R.J. (Richard), and Hirschhorn, J.N. (Joel)

Abstract

The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951 subjects (317 CD patient-parent trios) for 64 polymorphisms within 14 CD-susceptibility and 23 stature-associated loci. Patient height-for-age Z-score < -1.64 was used to dichotomize probands into growth-impaired and nongrowth-impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height-for-age Z-score < -1.64) and a stature-related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57-6.51], p = 0.0007). In addition, there was nominal over-transmission of two CD-susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth-impaired CD children (OR = 2.36, CI [1.26-4.41] p = 0.0056 and OR = 2.45, CI [1.22-4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD. © 2010 The Authors Annals of Human Genetics

Published
2010
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43. Common variants at five new loci associated with early-onset inflammatory bowel disease.

Author

Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, Dewit, Olivier, Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, and Dewit, Olivier

Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2009

44. 15 Serious infections and associated risk factors in patients receiving infliximab and immunotherapies for children with inflammatory bowel disease: DEVELOP registry data

Author

Baldassano, R., primary, Colletti, R., additional, Cucchiara, S., additional, Dubinsky, M., additional, Escher, J., additional, Faubion, W., additional, Fell, J., additional, Gold, B., additional, Griffiths, A., additional, Hyams, J., additional, Koletzko, S., additional, Kugathasan, S., additional, Markowitz, J., additional, Ruemmele, F.M., additional, Veereman, G., additional, Callegari, P., additional, Molenda, M., additional, Tang, K.L., additional, Wright, R., additional, and Winter, H., additional

Published
2013
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45. P436 Malignancies in children receiving infliximab and other inflammatory bowel disease therapies: an inflammatory bowel disease multicenter, prospective, long-term registry of pediatric patients (DEVELOP) registry data

Author

Colletti, R., primary, Cucchiara, S., additional, Dubinsky, M., additional, Escher, J., additional, Faubion, W., additional, Fell, J., additional, Gold, B., additional, Griffiths, A., additional, Hyams, J., additional, Koletzko, S., additional, Kugathasan, S., additional, Winter, H., additional, Baldassano, R., additional, Markowitz, J., additional, Ruemmele, F.M., additional, Callegari, P., additional, Molenda, M., additional, Tang, L., additional, Wright, R., additional, and Veereman, G., additional

Published
2013
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47. Crohn's Disease and Genetic Hitchhiking at IBD5

Author

Huff, C. D., primary, Witherspoon, D. J., additional, Zhang, Y., additional, Gatenbee, C., additional, Denson, L. A., additional, Kugathasan, S., additional, Hakonarson, H., additional, Whiting, A., additional, Davis, C. T., additional, Wu, W., additional, Xing, J., additional, Watkins, W. S., additional, Bamshad, M. J., additional, Bradfield, J. P., additional, Bulayeva, K., additional, Simonson, T. S., additional, Jorde, L. B., additional, and Guthery, S. L., additional

Published
2011
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50. Authors' reply

Author

Kugathasan, S., Saubermann, L.J., Smith, L., Kou, D., Itoh, J., Binion, D.G., Levine, A.D., Blumberg, R.S., and Fiocchi, C.

Subjects
Inflammatory bowel diseases -- Development and progression, Interleukin-12 -- Physiological aspects, Dendritic cells -- Physiological aspects, Health
Published
2008

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