Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.
Deutsch, Aaron J
Lenz, Tobias L
de Bakker, Paul IW
Rich, Stephen S
Springer Science and Business Media LLC
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Hu, X., Deutsch, A. J., Lenz, T. L., Onengut-Gumuscu, S., Han, B., Chen, W., Howson, J., et al. (2015). Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.. Nat Genet, 47 898-905. https://doi.org/10.1038/ng.3353
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.
Type 1 diabetes, MHC, HLA, amino acids, interaction
This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This work is supported in part by funding from the National Institutes of Health (5R01AR062886-02 (PIdB), 1R01AR063759 (SR), 5U01GM092691-05 (SR), 1UH2AR067677-01 (SR), R01AR065183 (PIWdB)), a Doris Duke Clinical Scientist Development Award (SR), the Wellcome Trust (JAT) and the National Institute for Health Research (JAT and JMMH), and a Vernieuwingsimpuls VIDI Award (016.126.354) from the Netherlands Organization for Scientific Research (PIWdB). TLL was supported by the German Research Foundation (LE 2593/1-1 and LE 2593/2-1).
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK062418)
Medical Research Council (MR/L003120/1)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)
British Heart Foundation (None)
External DOI: https://doi.org/10.1038/ng.3353
This record's URL: https://www.repository.cam.ac.uk/handle/1810/249202