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

Lenz, T. L., Deutsch, A. J., Han, B., Hu, X., Okada, Y., Eyre, S., 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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-3D26-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-AFE6-C
Genre: Journal Article

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 Creators:
Lenz, Tobias L.1, Author              
Deutsch, Aaron J., Author
Han, Buhm, Author
Hu, Xinli, Author
Okada, Yukinori, Author
Eyre, Stephen, Author
Knapp, Michael, Author
Zhernakova, Alexandra, Author
Huizinga, Tom W. J., Author
Abecasis, Gonçalo, Author
Becker, Jessica, Author
Boeckxstaens, Guy E, Author
Chen, Wei-Min, Author
Franke, Andre, Author
Gladman, Dafna D., Author
Gockel, Ines, Author
Gutierrez-Achury, Javier, Author
Martin, Javier, Author
Nair, Rajan P., Author
Nöthen, Markus M., Author
Onengut-Gumuscu, Suna, AuthorRahman, Proton, AuthorRantapää-Dahlqvist, Solbritt, AuthorStuart, Philip E., AuthorTsoi, Lam C., Authorvan Heel, David A., AuthorWorthington, Jane, AuthorWouters, Mira M., AuthorKlareskog, Lars, AuthorElder, James T., AuthorGregersen, Peter K., AuthorSchumacher, Johannes, AuthorRich, Stephen S., AuthorWijmenga, Cisca, AuthorSunyaev, Shamil R., Authorde Bakker, Paul I. W., AuthorRaychaudhuri, Soumya, Author more..
Affiliations:
1Emmy Noether Research Group Evolutionary Immunogenomics, Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2068286              

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 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 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11 11 ,11 5). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 1 10−12; T1D, P = 2.4 × 1 10−10; psoriasis, P = 5.9 × 1 10−6; celiac disease, P = 1 1.2 × 1 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 1.8 × 1 10−3; T1D, P = 8.6 × 1 10−27; celiac disease, P = 6.0 × 1 10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.

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Language(s): eng - English
 Dates: 2015-02-122015-07-162015-08-102015-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
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 Rev. Method: -
 Identifiers: DOI: 10.1038/ng.3379
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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 47 (9) Sequence Number: - Start / End Page: 1085 - 1090 Identifier: ISSN: 1061-4036 (print)
ISSN: 1546-1718 (online)
CoNE: /journals/resource/954925598609