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

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

doi:10.1038/ng.3353

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

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

MPS-Authors

/persons/resource/persons56796

Lenz, Tobias L.
Research Group Evolutionary Immunogenomics, Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

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.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-2D64-6

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.