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- Title
Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.
- Authors
Deutsch, Aaron J; Hu, Xinli; Gladman, Dafna D; Rantapää-Dahlqvist, Solbritt; Worthington, Jane; Klareskog, Lars; Knapp, Michael; Stuart, Philip E; Eyre, Stephen; Onengut-Gumuscu, Suna; Becker, Jessica; Gregersen, Peter K; Gutierrez-Achury, Javier; Wijmenga, Cisca; Rich, Stephen S; Gockel, Ines; Martin, Javier; Okada, Yukinori; Elder, James T; Sunyaev, Shamil R
- Abstract
Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10−12; T1D, P = 2.4 × 10−10; psoriasis, P = 5.9 × 10−6; celiac disease, P = 1.2 × 10−87). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10−3; T1D, P = 8.6 × 10−27; celiac disease, P = 6.0 × 10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.
- Subjects
HLA histocompatibility antigens; AUTOIMMUNE diseases; ALLELES; GENETIC carriers; SINGLE nucleotide polymorphisms
- Publication
Nature Genetics, 2015, Vol 47, Issue 9, p1085
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.3379