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  Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

Hu, X., Deutsch, A. J., Lenz, T. L., Onengut-Gumuscu, S., Han, B., Chen, W.-M., et al. (2015). Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nature Genetics, 47(8), 898-905. doi:10.1038/ng.3353.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-2D64-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-AFE9-6
Genre: Journal Article

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 Creators:
Hu, Xinli, Author
Deutsch, Aaron J., Author
Lenz, Tobias L.1, Author              
Onengut-Gumuscu, Suna, Author
Han, Buhm, Author
Chen, Wei-Min, Author
Howson, Joanna M. M., Author
Todd, John A., Author
de Bakker, Paul I. W., Author
Rich, Stephen S., Author
Raychaudhuri, Soumya, Author
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: Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQ1 position 57 (previously known; P = 1 × 10−1,355) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DR1 positions 13 (P = 1 × 10−721) and 71 (P = 1 × 10−95) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1–HLA-DQA1–HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1–HLA-DQA1–HLA-DQB1 haplotypes (P = 1.6 × 10−64). HLA-DR1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.

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Language(s): eng - English
 Dates: 2015-03-122015-06-172015-07-132015-08
 Publication Status: Published in print
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 Identifiers: DOI: 10.1038/ng.3353
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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 (8) Sequence Number: - Start / End Page: 898 - 905 Identifier: ISSN: 1061-4036 (print)
ISSN: 1546-1718 (online)
CoNE: /journals/resource/954925598609