Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
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Author
Lenz, Tobias L.
Han, Buhm
Okada, Yukinori
Eyre, Stephen
Knapp, Michael
Zhernakova, Alexandra
Huizinga, Tom W.J.
Abecasis, Goncalo
Becker, Jessica
Boeckxstaens, Guy E.
Chen, Wei-Min
Franke, Andre
Gladman, Dafna D.
Gockel, Ines
Gutierrez-Achury, Javier
Martin, Javier
Nair, Rajan P.
Nöthen, Markus M.
Onengut-Gumuscu, Suna
Rahman, Proton
Rantapää-Dahlqvist, Solbritt
Stuart, Philip E.
Tsoi, Lam C.
Van Heel, David A.
Worthington, Jane
Wouters, Mira M.
Klareskog, Lars
Elder, James T.
Gregersen, Peter K.
Schumacher, Johannes
Rich, Stephen S.
Wijmenga, Cisca
de Bakker, Paul I.W.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ng.3379Metadata
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Lenz, T. L., A. J. Deutsch, B. Han, X. Hu, Y. Okada, S. Eyre, M. Knapp, et al. 2015. “Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.” Nature genetics 47 (9): 1085-1090. doi:10.1038/ng.3379. http://dx.doi.org/10.1038/ng.3379.Abstract
Human leukocyte antigen (HLA) genes confer strong 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 may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, 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 out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; 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 dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model).Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552599/pdf/Terms of Use
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