Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

被引：96

作者：

Miller, F. W. ^{[1
]}

Chen, W. ^{[2
]}

O'Hanlon, T. P. ^{[1
]}

Cooper, R. G. ^{[3
]}

Vencovsky, J. ^{[4
]}

Rider, L. G. ^{[1
]}

Danko, K. ^{[5
]}

Wedderburn, L. R. ^{[6
]}

Lundberg, I. E. ^{[7
]}

Pachman, L. M. ^{[8
]}

Reed, A. M. ^{[9
]}

Ytterberg, S. R. ^{[9
]}

Padyukov, L. ^{[7
]}

Selva-O'Callaghan, A. ^{[10
]}

Radstake, T. R. ^{[11
,12
]}

Isenberg, D. A. ^{[13
]}

Chinoy, H. ^{[14
]}

Ollier, W. E. R. ^{[15
]}

Scheet, P. ^{[2
]}

Peng, B. ^{[2
]}

Lee, A. ^{[16
]}

Byun, J. ^{[17
]}

Lamb, J. A. ^{[15
]}

Gregersen, P. K. ^{[16
]}

Amos, C. I. ^{[17
]}

机构：

[1] NIEHS, NIH, Bethesda, MD 20892 USA

[2] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[3] Univ Liverpool, MRC ARUK Inst Ageing & Chron Dis, Liverpool L69 3BX, Merseyside, England

[4] Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic

[5] Univ Debrecen, Div Immunol, Dept Internal Med 3, Debrecen, Hungary

[6] UCL, Inst Child Hlth, London, England

[7] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden

[8] Northwestern Univ, Feinberg Sch Med, Dept Pediat Rheumatol, Chicago, IL 60611 USA

[9] Mayo Clin, Rochester, MN USA

[10] Vall dHebron Gen Hosp, Barcelona, Spain

[11] Univ Utrecht, Med Ctr, Lab Translat Immunol, Dept Rheumatol & Clin Immunol, NL-3508 TC Utrecht, Netherlands

[12] Nijmegen Ctr Mol Life Sci, Nijmegen, Netherlands

[13] UCL, Div Med, London, England

[14] Univ Manchester, Natl Inst Hlth Res, Manchester Musculoskeletal Biomed Res Unit, Ctr Musculoskeletal Res, Manchester, Lancs, England

[15] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[16] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA

[17] Dartmouth Coll, Dept Community & Family Med, Hanover, NH 03755 USA

来源：

GENES AND IMMUNITY | 2015年 / 16卷 / 07期

基金：

英国惠康基金; 瑞典研究理事会;

关键词：

IDIOPATHIC INFLAMMATORY MYOPATHIES; IMMUNE-RESPONSE; COMPLEX; AUTOANTIBODIES; DISEASE; LINKAGE; IMMUNOGENETICS; PATHOGENESIS; POLYMYOSITIS; ANTIBODIES;

D O I：

10.1038/gene.2015.28

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5x10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

引用

页码：470 / 480

页数：11

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