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

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Jostins, Luke Ripke, Stephan Weersma, Rinse K Duerr, Richard H McGovern, Dermot P Rahier, Jean-François [UCL]

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2012
Language Anglais
Journal information "Nature" - Vol. 491, no. 7422, p. 119-124 (2012)
Peer reviewed yes
Publisher Nature Publishing Group
issn 0028-0836
e-issn 1476-4687
Publication status Publié
Affiliations UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie
UCL - (MGD) Service de gastro-entérologie
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  1. Molodecky Natalie A., Soon Ing Shian, Rabi Doreen M., Ghali William A., Ferris Mollie, Chernoff Greg, Benchimol Eric I., Panaccione Remo, Ghosh Subrata, Barkema Herman W., Kaplan Gilaad G., Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review, 10.1053/j.gastro.2011.10.001
  2. Anderson Carl A, Boucher Gabrielle, Lees Charlie W, Franke Andre, D'Amato Mauro, Taylor Kent D, Lee James C, Goyette Philippe, Imielinski Marcin, Latiano Anna, Lagacé Caroline, Scott Regan, Amininejad Leila, Bumpstead Suzannah, Baidoo Leonard, Baldassano Robert N, Barclay Murray, Bayless Theodore M, Brand Stephan, Büning Carsten, Colombel Jean-Frédéric, Denson Lee A, De Vos Martine, Dubinsky Marla, Edwards Cathryn, Ellinghaus David, Fehrmann Rudolf S N, Floyd James A B, Florin Timothy, Franchimont Denis, Franke Lude, Georges Michel, Glas Jürgen, Glazer Nicole L, Guthery Stephen L, Haritunians Talin, Hayward Nicholas K, Hugot Jean-Pierre, Jobin Gilles, Laukens Debby, Lawrance Ian, Lémann Marc, Levine Arie, Libioulle Cecile, Louis Edouard, McGovern Dermot P, Milla Monica, Montgomery Grant W, Morley Katherine I, Mowat Craig, Ng Aylwin, Newman William, Ophoff Roel A, Papi Laura, Palmieri Orazio, Peyrin-Biroulet Laurent, Panés Julián, Phillips Anne, Prescott Natalie J, Proctor Deborah D, Roberts Rebecca, Russell Richard, Rutgeerts Paul, Sanderson Jeremy, Sans Miquel, Schumm Philip, Seibold Frank, Sharma Yashoda, Simms Lisa A, Seielstad Mark, Steinhart A Hillary, Targan Stephan R, van den Berg Leonard H, Vatn Morten, Verspaget Hein, Walters Thomas, Wijmenga Cisca, Wilson David C, Westra Harm-Jan, Xavier Ramnik J, Zhao Zhen Z, Ponsioen Cyriel Y, Andersen Vibeke, Torkvist Leif, Gazouli Maria, Anagnou Nicholas P, Karlsen Tom H, Kupcinskas Limas, Sventoraityte Jurgita, Mansfield John C, Kugathasan Subra, Silverberg Mark S, Halfvarson Jonas, Rotter Jerome I, Mathew Christopher G, Griffiths Anne M, Gearry Richard, Ahmad Tariq, Brant Steven R, Chamaillard Mathias, Satsangi Jack, Cho Judy H, Schreiber Stefan, Daly Mark J, Barrett Jeffrey C, Parkes Miles, Annese Vito, Hakonarson Hakon, Radford-Smith Graham, Duerr Richard H, Vermeire Séverine, Weersma Rinse K, Rioux John D, Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, 10.1038/ng.764
  3. Franke Andre, McGovern Dermot P B, Barrett Jeffrey C, Wang Kai, Radford-Smith Graham L, Ahmad Tariq, Lees Charlie W, Balschun Tobias, Lee James, Roberts Rebecca, Anderson Carl A, Bis Joshua C, Bumpstead Suzanne, Ellinghaus David, Festen Eleonora M, Georges Michel, Green Todd, Haritunians Talin, Jostins Luke, Latiano Anna, Mathew Christopher G, Montgomery Grant W, Prescott Natalie J, Raychaudhuri Soumya, Rotter Jerome I, Schumm Philip, Sharma Yashoda, Simms Lisa A, Taylor Kent D, Whiteman David, Wijmenga Cisca, Baldassano Robert N, Barclay Murray, Bayless Theodore M, Brand Stephan, Büning Carsten, Cohen Albert, Colombel Jean-Frederick, Cottone Mario, Stronati Laura, Denson Ted, De Vos Martine, D'Inca Renata, Dubinsky Marla, Edwards Cathryn, Florin Tim, Franchimont Denis, Gearry Richard, Glas Jürgen, Van Gossum Andre, Guthery Stephen L, Halfvarson Jonas, Verspaget Hein W, Hugot Jean-Pierre, Karban Amir, Laukens Debby, Lawrance Ian, Lemann Marc, Levine Arie, Libioulle Cecile, Louis Edouard, Mowat Craig, Newman William, Panés Julián, Phillips Anne, Proctor Deborah D, Regueiro Miguel, Russell Richard, Rutgeerts Paul, Sanderson Jeremy, Sans Miquel, Seibold Frank, Steinhart A Hillary, Stokkers Pieter C F, Torkvist Leif, Kullak-Ublick Gerd, Wilson David, Walters Thomas, Targan Stephan R, Brant Steven R, Rioux John D, D'Amato Mauro, Weersma Rinse K, Kugathasan Subra, Griffiths Anne M, Mansfield John C, Vermeire Severine, Duerr Richard H, Silverberg Mark S, Satsangi Jack, Schreiber Stefan, Cho Judy H, Annese Vito, Hakonarson Hakon, Daly Mark J, Parkes Miles, Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci, 10.1038/ng.717
  4. Khor Bernard, Gardet Agnès, Xavier Ramnik J., Genetics and pathogenesis of inflammatory bowel disease, 10.1038/nature10209
  5. Cho Judy H., Gregersen Peter K., Genomics and the Multifactorial Nature of Human Autoimmune Disease, 10.1056/nejmra1100030
  6. Cortes Adrian, Brown Matthew A, Promise and pitfalls of the Immunochip, 10.1186/ar3204
  7. Zuk O., Hechter E., Sunyaev S. R., Lander E. S., The mystery of missing heritability: Genetic interactions create phantom heritability, 10.1073/pnas.1119675109
  8. Raychaudhuri Soumya, Plenge Robert M., Rossin Elizabeth J., Ng Aylwin C. Y., Purcell Shaun M., Sklar Pamela, Scolnick Edward M., Xavier Ramnik J., Altshuler David, Daly Mark J., , Identifying Relationships among Genomic Disease Regions: Predicting Genes at Pathogenic SNP Associations and Rare Deletions, 10.1371/journal.pgen.1000534
  9. Hindorff L. A., Sethupathy P., Junkins H. A., Ramos E. M., Mehta J. P., Collins F. S., Manolio T. A., Potential etiologic and functional implications of genome-wide association loci for human diseases and traits, 10.1073/pnas.0903103106
  10. Notarangelo Luigi D., Fischer Alain, Geha Raif S., Casanova Jean-Laurent, Chapel Helen, Conley Mary Ellen, Cunningham-Rundles Charlotte, Etzioni Amos, Hammartröm Lennart, Nonoyama Shigeaki, Ochs Hans D., Puck Jennifer, Roifman Chaim, Seger Reinhard, Wedgwood Josiah, Primary immunodeficiencies: 2009 update, 10.1016/j.jaci.2009.10.013
  11. Bustamante Jacinta, Picard Capucine, Boisson-Dupuis Stéphanie, Abel Laurent, Casanova Jean-Laurent, Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases : X-linked susceptibility to mycobacterial diseases, 10.1111/j.1749-6632.2011.06273.x
  12. Patel S Y, Doffinger R, Barcenas-Morales G, Kumararatne D S, Genetically determined susceptibility to mycobacterial infection, 10.1136/jcp.2007.051201
  13. Zhang Furen, Liu Hong, Chen Shumin, Low Huiqi, Sun Liangdan, Cui Yong, Chu Tongsheng, Li Yi, Fu Xi'an, Yu Yongxiang, Yu Gongqi, Shi Benqing, Tian Hongqing, Liu Dianchang, Yu Xiulu, Li Jinghui, Lu Nan, Bao Fangfang, Yuan Chunying, Liu Jian, Liu Huaxu, Zhang Lin, Sun Yonghu, Chen Mingfei, Yang Qing, Yang Haitao, Yang Rongde, Zhang Lianhua, Wang Qiang, Liu Hong, Zuo Fuguang, Zhang Haizhen, Khor Chiea Chuen, Hibberd Martin L, Yang Sen, Liu Jianjun, Zhang Xuejun, Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy, 10.1038/ng.973
  14. Holland Steven M., DeLeo Frank R., Elloumi Houda Z., Hsu Amy P., Uzel Gulbu, Brodsky Nina, Freeman Alexandra F., Demidowich Andrew, Davis Joie, Turner Maria L., Anderson Victoria L., Darnell Dirk N., Welch Pamela A., Kuhns Douglas B., Frucht David M., Malech Harry L., Gallin John I., Kobayashi Scott D., Whitney Adeline R., Voyich Jovanka M., Musser James M., Woellner Cristina, Schäffer Alejandro A., Puck Jennifer M., Grimbacher Bodo, STAT3Mutations in the Hyper-IgE Syndrome, 10.1056/nejmoa073687
  15. Minegishi Yoshiyuki, Saito Masako, Tsuchiya Shigeru, Tsuge Ikuya, Takada Hidetoshi, Hara Toshiro, Kawamura Nobuaki, Ariga Tadashi, Pasic Srdjan, Stojkovic Oliver, Metin Ayse, Karasuyama Hajime, Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome, 10.1038/nature06096
  16. Glocker Erik-Oliver, Hennigs Andre, Nabavi Mohammad, Schäffer Alejandro A., Woellner Cristina, Salzer Ulrich, Pfeifer Dietmar, Veelken Hendrik, Warnatz Klaus, Tahami Fariba, Jamal Sarah, Manguiat Annabelle, Rezaei Nima, Amirzargar Ali Akbar, Plebani Alessandro, Hannesschläger Nicole, Gross Olaf, Ruland Jürgen, Grimbacher Bodo, A HomozygousCARD9Mutation in a Family with Susceptibility to Fungal Infections, 10.1056/nejmoa0810719
  17. Hu Xinli, Kim Hyun, Stahl Eli, Plenge Robert, Daly Mark, Raychaudhuri Soumya, Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets, 10.1016/j.ajhg.2011.09.002
  18. Zhang B., Stat. Appl. Genet. Mol. Biol., 4, Article 17 (2005)
  19. Greenawalt D. M., Dobrin R., Chudin E., Hatoum I. J., Suver C., Beaulaurier J., Zhang B., Castro V., Zhu J., Sieberts S. K., Wang S., Molony C., Heymsfield S. B., Kemp D. M., Reitman M. L., Lum P. Y., Schadt E. E., Kaplan L. M., A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort, 10.1101/gr.112821.110
  20. Emilsson Valur, Thorleifsson Gudmar, Zhang Bin, Leonardson Amy S., Zink Florian, Zhu Jun, Carlson Sonia, Helgason Agnar, Walters G. Bragi, Gunnarsdottir Steinunn, Mouy Magali, Steinthorsdottir Valgerdur, Eiriksdottir Gudrun H., Bjornsdottir Gyda, Reynisdottir Inga, Gudbjartsson Daniel, Helgadottir Anna, Jonasdottir Aslaug, Jonasdottir Adalbjorg, Styrkarsdottir Unnur, Gretarsdottir Solveig, Magnusson Kristinn P., Stefansson Hreinn, Fossdal Ragnheidur, Kristjansson Kristleifur, Gislason Hjortur G., Stefansson Tryggvi, Leifsson Bjorn G., Thorsteinsdottir Unnur, Lamb John R., Gulcher Jeffrey R., Reitman Marc L., Kong Augustine, Schadt Eric E., Stefansson Kari, Genetics of gene expression and its effect on disease, 10.1038/nature06758
  21. Schadt Eric E, Molony Cliona, Chudin Eugene, Hao Ke, Yang Xia, Lum Pek Y, Kasarskis Andrew, Zhang Bin, Wang Susanna, Suver Christine, Zhu Jun, Millstein Joshua, Sieberts Solveig, Lamb John, GuhaThakurta Debraj, Derry Jonathan, Storey John D, Avila-Campillo Iliana, Kruger Mark J, Johnson Jason M, Rohl Carol A, van Nas Atila, Mehrabian Margarete, Drake Thomas A, Lusis Aldons J, Smith Ryan C, Guengerich F. Peter, Strom Stephen C, Schuetz Erin, Rushmore Thomas H, Ulrich Roger, Mapping the Genetic Architecture of Gene Expression in Human Liver, 10.1371/journal.pbio.0060107
  22. Chen Yanqing, Zhu Jun, Lum Pek Yee, Yang Xia, Pinto Shirly, MacNeil Douglas J., Zhang Chunsheng, Lamb John, Edwards Stephen, Sieberts Solveig K., Leonardson Amy, Castellini Lawrence W., Wang Susanna, Champy Marie-France, Zhang Bin, Emilsson Valur, Doss Sudheer, Ghazalpour Anatole, Horvath Steve, Drake Thomas A., Lusis Aldons J., Schadt Eric E., Variations in DNA elucidate molecular networks that cause disease, 10.1038/nature06757
  23. Zhong Hua, Beaulaurier John, Lum Pek Yee, Molony Cliona, Yang Xia, MacNeil Douglas J., Weingarth Drew T., Zhang Bin, Greenawalt Danielle, Dobrin Radu, Hao Ke, Woo Sangsoon, Fabre-Suver Christine, Qian Su, Tota Michael R., Keller Mark P., Kendziorski Christina M., Yandell Brian S., Castro Victor, Attie Alan D., Kaplan Lee M., Schadt Eric E., Liver and Adipose Expression Associated SNPs Are Enriched for Association to Type 2 Diabetes, 10.1371/journal.pgen.1000932
  24. Zhu Jun, Wiener Matthew C., Zhang Chunsheng, Fridman Arthur, Minch Eric, Lum Pek Y., Sachs Jeffrey R., Schadt Eric E., Increasing the Power to Detect Causal Associations by Combining Genotypic and Expression Data in Segregating Populations, 10.1371/journal.pcbi.0030069
  25. Lewis S. J., Int. J. Tuberc. Lung Dis., 9, 1174 (2005)
  26. Li XiangWei, Yang Yu, Zhou Feng, Zhang Yunzhi, Lu Hongzhou, Jin Qi, Gao Lei, SLC11A1 (NRAMP1) Polymorphisms and Tuberculosis Susceptibility: Updated Systematic Review and Meta-Analysis, 10.1371/journal.pone.0015831
  27. Kumar Dhiraj, Nath Lekha, Kamal Md. Azhar, Varshney Ankur, Jain Avinash, Singh Sarman, Rao Kanury V.S., Genome-wide Analysis of the Host Intracellular Network that Regulates Survival of Mycobacterium tuberculosis, 10.1016/j.cell.2010.02.012
  28. Glocker Erik-Oliver, Frede Natalie, Perro Mario, Sebire Neil, Elawad Mamoun, Shah Neil, Grimbacher Bodo, Infant colitis—it's in the genes, 10.1016/s0140-6736(10)61008-2
  29. Franke Andre, Balschun Tobias, Karlsen Tom H, Sventoraityte Jurgita, Nikolaus Susanna, Mayr Gabriele, Domingues Francisco S, Albrecht Mario, Nothnagel Michael, Ellinghaus David, Sina Christian, Onnie Clive M, Weersma Rinse K, Stokkers Pieter C F, Wijmenga Cisca, Gazouli Maria, Strachan David, McArdle Wendy L, Vermeire Séverine, Rutgeerts Paul, Rosenstiel Philip, Krawczak Michael, Vatn Morten H, Mathew Christopher G, Schreiber Stefan, Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility, 10.1038/ng.221
  30. Bhattacharjee Ashish, Pal Srabani, Feldman Gerald M., Cathcart Martha K., Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes, 10.1074/jbc.m111.291492
Bibliographic reference Jostins, Luke ; Ripke, Stephan ; Weersma, Rinse K ; Duerr, Richard H ; McGovern, Dermot P ; et. al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.. In: Nature, Vol. 491, no. 7422, p. 119-124 (2012)
Permanent URL http://hdl.handle.net/2078.1/118342