Abstract
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<5 × 10-8) 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.
Original language | English (US) |
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Pages (from-to) | 470-480 |
Number of pages | 11 |
Journal | Genes and Immunity |
Volume | 16 |
Issue number | 7 |
DOIs | |
State | Published - Oct 1 2015 |
Funding
This study was supported in part by: the Intramural Program of the NIH, National Institute of Environmental Health Sciences (NIEHS Z01ES101074); European Community’s FP6, AutoCure LSHB CT-2006-018661; Myositis UK; Arthritis Research UK (18474 and 20164); The Cure JM Foundation; the European Science Foundation in the framework of the Research Networking Programme European Myositis Network (EuMyoNet); Association Francaise Contre Les Myopathies (AFM), the National Institute for Health Research Biomedical Research Centre at ICH/GOSH; the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit; the Wellcome Trust; Action Medical UK; Great Ormond Street Children’s Charity; the National Institute for Health Research Translational Research Collaboration on rare diseases; and the Swedish Research Council. The Czech cohort was partially supported by the Ministry of Health, Czech Republic (No. 00023728).
ASJC Scopus subject areas
- Immunology
- Genetics
- Genetics(clinical)