Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

Authors:
Tobias L Lenz, Aaron J Deutsch, Buhm Han, Xinli Hu, Yukinori Okada, Stephen Eyre, Michael Knapp, Alexandra Zhernakova, Tom W J Huizinga, Gonçalo Abecasis, Jessica Becker, Guy E Boeckxstaens, Wei-Min Chen, Andre Franke, Dafna D Gladman, Ines Gockel, Javier Gutierrez-Achury, Javier Martin, Rajan P Nair, Markus M Nöthen, Suna Onengut-Gumuscu, Proton Rahman, Solbritt Rantapää-Dahlqvist, Philip E Stuart, Lam C Tsoi, David A van Heel, Jane Worthington, Mira M Wouters, Lars Klareskog, James T Elder, Peter K Gregersen, Johannes Schumacher, Stephen S Rich, Cisca Wijmenga, Shamil R Sunyaev, Paul I W de Bakker, Soumya Raychaudhuri
Year of publication:
2015
Volume:
47
Issue:
9
Issn:
1061-4036
Journal title abbreviated:
NAT GENET
Journal title long:
Nature genetics
Impact factor:
31.616
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.