Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

被引：287

作者：

Hinks, Anne ^{[1
,2
]}

Cobb, Joanna ^{[1
,2
]}

Marion, Miranda C. ^{[3
,4
]}

Prahalad, Sampath ^{[5
,6
]}

Sudman, Marc ^{[7
]}

Bowes, John ^{[1
,2
]}

Martin, Paul ^{[1
,2
]}

Comeau, Mary E. ^{[3
,4
]}

Sajuthi, Satria ^{[3
,4
]}

Andrews, Robert ^{[8
]}

Brown, Milton ^{[5
]}

Chen, Wei-Min ^{[9
]}

Concannon, Patrick ^{[9
]}

Deloukas, Panos ^{[8
]}

Edkins, Sarah ^{[8
]}

Eyre, Stephen ^{[1
,2
]}

Gaffney, Patrick M. ^{[10
]}

Guthery, Stephen L. ^{[11
,12
]}

Guthridge, Joel M. ^{[10
]}

Hunt, Sarah E. ^{[8
]}

James, Judith A. ^{[10
]}

Keddache, Mehdi ^{[13
]}

Moser, Kathy L. ^{[10
]}

Nigrovic, Peter A. ^{[14
,15
]}

Onengut-Gumuscu, Suna ^{[9
]}

Onslow, Mitchell L. ^{[7
]}

Rose, Carlos D. ^{[14
,15
]}

Rich, Stephen S. ^{[9
]}

Steel, Kathryn J. A. ^{[1
,2
]}

Wakeland, Edward K. ^{[16
]}

Wallace, Carol A. ^{[17
]}

Wedderburn, Lucy R. ^{[18
]}

Woo, Patricia ^{[19
]}

Bohnsack, John F. ^{[11
,12
]}

Haas, Johannes Peter ^{[20
]}

Glass, David N. ^{[7
]}

Langefeld, Carl D. ^{[3
,4
]}

Thomson, Wendy ^{[1
,2
]}

Thompson, Susan D. ^{[7
]}

机构：

[1] Univ Manchester, Arthrit Res UK Epidemiol Unit, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[2] Cent Manchester Univ Hosp Natl Hlth Serv Fdn Trus, Natl Inst Hlth Res, Manchester Musculoskeletal Biomed Res Unit, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[3] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA

[4] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA

[5] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA

[6] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[7] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH USA

[8] Wellcome Trust Sanger Inst, Cambridge, England

[9] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[10] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Program, Oklahoma City, OK 73104 USA

[11] Univ Utah, Dept Pediat, Salt Lake City, UT USA

[12] Univ Utah, Sch Med, Salt Lake City, UT USA

[13] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA

[14] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[15] Boston Childrens Hosp, Div Immunol, Boston, MA USA

[16] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA

[17] Seattle Childrens Hosp & Res Inst, Dept Pediat, Seattle, WA USA

[18] UCL Inst Child Hlth, Rheumatol Unit, London, England

[19] UCL, Div Infect & Immun, London, England

[20] German Ctr Rheumatol Children & Young People, Garmisch Partenkirchen, Germany

来源：

NATURE GENETICS | 2013年 / 45卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; GENE-EXPRESSION; CCR5; GENE; COMMON; POPULATION; RISK; VARIANTS; STAT4;

D O I：

10.1038/ng.2614

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 x 10(-8)) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 x 10(-6)). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 x 10(-6)) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

引用

页码：664 / +

页数：8

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