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

被引：267

作者：

Goyette, Philippe ^{[1
]}

Boucher, Gabrielle ^{[1
]}

Mallon, Dermot ^{[2
,3
]}

Ellinghaust, Eva ^{[4
]}

Jostins, Luke

Huang, Hailiang ^{[5
,6
]}

Ripke, Stephan ^{[5
,6
]}

Gusareva, Elena S. ^{[7
,8
]}

Annese, Vito ^{[9
,10
]}

Hauser, Stephen L. ^{[11
]}

Oksenberg, Jorge R. ^{[11
]}

Thomsent, Ingo ^{[4
,12
]}

Leslie, Stephen ^{[12
,13
]}

Daly, Mark J. ^{[5
,6
]}

Van Steen, Kristel ^{[7
,8
]}

Duerr, Richard H. ^{[14
,15
]}

Barrett, Jeffrey C.

McGovern, Dermot P. B. ^{[16
]}

Schumm, L. Philip ^{[17
]}

Traherne, James A. ^{[18
,19
]}

Carrington, Mary N. ^{[20
,21
]}

Kosmoliaptsis, Vasilis ^{[2
,3
]}

Karsen, Tom H. ^{[22
,23
,24
]}

Franke, Andre ^{[4
]}

Rioux, John D. ^{[1
,25
]}

机构：

[1] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

[2] Univ Cambridge, Dept Surg, Cambridge, England

[3] Cambridge Biomed Res Ctr, NIHR, Cambridge, England

[4] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA USA

[7] Univ Liege, Inst Montefiore, Syst & Modeling Unit, B-4000 Liege, Belgium

[8] Univ Liege, GIGA R Grp Interdisciplinaire Genoproteom Appl Re, Liege, Belgium

[9] IRCCS CSS Hosp, Gastroenterol Unit, San Giovanni Rotondo, Italy

[10] Azienda Osped Univ AOU Careggi, Strut Org Dipartimentali, Unit Gastroenterol SOD2, Florence, Italy

[11] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[12] Murdoch Childrens Res Inst, Parkville, Vic, Australia

[13] Univ Melbourne, Dept Math & Stat, Melbourne, Vic, Australia

[14] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[15] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[16] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA

[17] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA

[18] Cambridge Inst Med Res, Cambridge, England

[19] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England

[20] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA

[21] Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA USA

[22] Oslo Univ Hosp, Rikshosp, Res Inst Internal Med, Dept Transplantat Med,Div Canc Surg & Transplanta, N-0450 Oslo, Norway

[23] Oslo Univ Hosp, Rikshosp, Norwegian Primary Sclerosing Cholangitis Res Ctr, Dept Transplantat Med,Div Canc Surg & Transplanta, N-0450 Oslo, Norway

[24] Univ Oslo, Inst Clin Med, KG Jebsen Inflammat Res Ctr, Oslo, Norway

[25] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

来源：

NATURE GENETICS | 2015年 / 47卷 / 02期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院; 美国医疗保健研究与质量局;

关键词：

PRIMARY SCLEROSING CHOLANGITIS; MAJOR HISTOCOMPATIBILITY COMPLEX; PROTEIN STRUCTURES; HLA-DR; SUSCEPTIBILITY; HAPLOTYPE; GENOTYPE; ALLELES; ASSOCIATION; VARIANTS;

D O I：

10.1038/ng.3176

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules(1). Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles2,3. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

引用

页码：172 / 179

页数：8

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