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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-08

AUTHORS

Xinli Hu, Aaron J Deutsch, Tobias L Lenz, Suna Onengut-Gumuscu, Buhm Han, Wei-Min Chen, Joanna M M Howson, John A Todd, Paul I W de Bakker, Stephen S Rich, Soumya Raychaudhuri

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-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 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-DRβ1 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. More... »

PAGES

898-905

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.3353

DOI

http://dx.doi.org/10.1038/ng.3353

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1049614939

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26168013


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