HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

被引：116

作者：

Ombrello, Michael J. ^{[1
]}

Remmers, Elaine F. ^{[2
]}

Tachmazidou, Ioanna ^{[3
]}

Grom, Alexei ^{[4
,5
]}

Foell, Dirk ^{[6
]}

Haas, Johannes-Peter ^{[7
]}

Martini, Alberto ^{[8
,9
]}

Gattorno, Marco ^{[9
]}

Ozen, Seza ^{[10
]}

Prahalad, Sampath ^{[11
,12
]}

Zeft, Andrew S. ^{[13
]}

Bohnsack, John F. ^{[14
]}

Mellins, Elizabeth D. ^{[15
]}

Ilowite, Norman T. ^{[16
,17
]}

Russo, Ricardo ^{[18
]}

Len, Claudio ^{[19
]}

Hilario, Maria Odete E. ^{[19
]}

Oliveira, Sheila ^{[20
]}

Yeung, Rae S. M. ^{[21
,22
,23
]}

Rosenberg, Alan ^{[24
]}

Wedderburn, Lucy R. ^{[25
,26
]}

Anton, Jordi ^{[27
]}

Schwarz, Tobias ^{[28
]}

Hinks, Anne ^{[29
]}

Bilginer, Yelda ^{[10
]}

Park, Jane ^{[15
]}

Cobb, Joanna ^{[29
,30
]}

Satorius, Colleen L. ^{[2
]}

Han, Buhm ^{[31
,32
,33
]}

Baskin, Elizabeth ^{[1
]}

Signa, Sara ^{[8
]}

Duerr, Richard H. ^{[34
,35
]}

Achkar, J. P. ^{[36
,37
]}

Kamboh, M. Ilyas ^{[34
]}

Kaufman, Kenneth M. ^{[4
,5
]}

Kottyan, Leah C. ^{[4
,5
]}

Pinto, Dalila ^{[38
]}

Scherer, Stephen W. ^{[39
]}

Alarcon-Riquelme, Marta E. ^{[40
,41
]}

Docampo, Elisa ^{[42
,43
,44
]}

Estivill, Xavier ^{[43
,44
]}

Gul, Ahmet ^{[45
]}

de Bakker, Paul I. W. ^{[46
,47
,48
]}

Raychaudhuri, Soumya ^{[29
,31
,32
]}

Langefeld, Carl D. ^{[49
]}

Thompson, Susan ^{[4
,5
]}

Zeggini, Eleftheria ^{[3
]}

Thomson, Wendy ^{[29
,30
]}

Kastner, Daniel L. ^{[2
]}

Woo, Patricia ^{[26
]}

机构：

[1] NIAMSD, Translat Genet & Genom Unit, NIH, Bethesda, MD 20892 USA

[2] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA

[3] Wellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1SA, England

[4] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA

[5] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[6] Univ Hosp Munster, Dept Pediat Rheumatol & Immunol, D-48149 Munster, Germany

[7] German Ctr Pediat & Adolescent Rheumatol, D-82467 Garmisch Partenkirchen, Germany

[8] Univ Genoa, Dept Pediat, I-16145 Genoa, Italy

[9] G Gaslini Inst Children, Pediat Unit 2, I-16147 Genoa, Italy

[10] Hacettepe Univ, Dept Pediat Rheumatol, TR-06100 Ankara, Turkey

[11] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA

[12] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[13] Cleveland Clin, Dept Pediat, Cleveland, OH 44195 USA

[14] Univ Utah, Dept Pediat, Salt Lake City, UT 84113 USA

[15] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[16] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA

[17] Childrens Hosp Montefiore, Bronx, NY 10461 USA

[18] Hosp Pediat Garrahan, Serv Immunol & Rheumatol, Buenos Aires, DF, Argentina

[19] Univ Fed Sao Paulo, Dept Pediat, BR-04021001 Sao Paulo, Brazil

[20] Univ Fed Rio de Janeiro, BR-21941901 Rio De Janeiro, Brazil

[21] Univ Toronto, Dept Pediat, Toronto, ON M5S 1A8, Canada

[22] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[23] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada

[24] Univ Saskatchewan, Dept Pediat, Saskatoon, SK S7N 0W8, Canada

[25] UCL, Inst Child Hlth, London WC1N 1EH, England

[26] UCL, Ctr Paediat & Adolescent Rheumatol, London WC1N 1EH, England

[27] Univ Barcelona, Hosp St Joan de Deu, Pediat Rheumatol Unit, Barcelona 08950, Spain

[28] Univ Wurzburg, Sect Pediat Rheumatol & Osteol, D-97080 Wurzburg, Germany

[29] Univ Manchester, Manchester Acad Hlth Ctr, Arthritis Res UK Ctr Genet & Genom, Manchester M13 9PT, Lancs, England

[30] Univ Manchester, Manchester Acad Hlth Ctr, Cent Manchester Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res Manchester Musculoskeletal Bio, Manchester M13 9PT, Lancs, England

[31] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA

[32] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Immunol Allergy & Rheumatol, Boston, MA 02115 USA

[33] Univ, Coll Med, Asan Med Ctr, Dept Convergence Med, Seoul 138736, South Korea

[34] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA

[35] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA

[36] Cleveland Clin, Dept Gastroenterol & Hepatol, Cleveland, OH 44195 USA

[37] Cleveland Clin, Dept Pathobiol, Cleveland, OH 44195 USA

[38] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[39] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 0A4, Canada

[40] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Program, Oklahoma City, OK 73104 USA

[41] Pfizer Univ Granada Andalusian Govt, Ctr Genom & Oncol Res, Pts Granada 18016, Spain

[42] Univ Liege, Interdisciplinary Cluster Appl Genoprot, B-4000 Cointe Ougree, Belgium

[43] Barcelona Inst Sci & Technol, CRG, Barcelona 08003, Spain

[44] UPF, Barcelona 08003, Spain

[45] Istanbul Univ, Istanbul Fac Med, TR-34390 Istanbul, Turkey

[46] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands

[47] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands

[48] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, NL-3584 CX Utrecht, Netherlands

[49] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27106 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 52期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

systemic juvenile idiopathic arthritis; Still's disease; human leukocyte antigen; autoinflammation; MACROPHAGE ACTIVATION SYNDROME; RHEUMATOID-ARTHRITIS; CHILDREN; ASSOCIATIONS; PATHOGENESIS; ABATACEPT; DISEASE; GENE;

D O I：

10.1073/pnas.1520779112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 x 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 x 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 x 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 x 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

引用

页码：15970 / 15975

页数：6

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