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Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
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2015 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 9, 1085-1090 p.Article in journal (Refereed) Published
Abstract [en]

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 (n(cases) = 5,337), type 1 diabetes (T1D; n(cases) = 5,567), psoriasis vulgaris (n(cases) = 3,089), idiopathic achalasia (n(cases) = 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 x 10(-12); T1D, P = 2.4 x 10(-10); psoriasis, P = 5.9 x 10(-6); celiac disease, P = 1.2 x 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 x 10(-3); T1D, P = 8.6 x 10(-27); celiac disease, P = 6.0 x 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.

Place, publisher, year, edition, pages
Macmillan Publishers Ltd., 2015. Vol. 47, no 9, 1085-1090 p.
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Public Health, Global Health, Social Medicine and Epidemiology
URN: urn:nbn:se:umu:diva-109376DOI: 10.1038/ng.3379ISI: 000360394100021PubMedID: 26258845OAI: diva2:857482
Available from: 2015-09-29 Created: 2015-09-25 Last updated: 2016-02-04Bibliographically approved

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