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

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.

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

“…These and other studies underscore the utility of trans -ancestral cohorts for fine-mapping genetic associations 51 . Similarly, for T1DM, a secondary association to DRβ1 at positions 13 and 71 explains much of the class II HLA association with T1DM, in addition to the well-known HLA-DQB1 position 57 association 23 . Certain regions in HLA proteins seem to recur in the context of HLA–disease associations; for example, the DRβ1 pocket 4 includes positions 13, 71 and 74, and has been implicated in antibody-negative RA and follicular lymphoma 52,53 in addition to T1DM and antibody-positive RA 23,48 .…”

“…The MHC locus contributes to autoimmune disease risk more significantly than do any other known loci. In T1DM, 30% of disease liability is attributed to the MHC locus, compared with 9% for other loci discovered across the rest of the genome with GWAS 23 . Although the MHC locus is a 3.6-Mb region comprising >250 genes 24 , most associations are mediated by a handful of human leukocyte antigen (HLA) genes (FIG.…”

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases

“…The method uses a large reference dataset collected by the type 1 diabetes genetics consortium10 (n=5225). This dataset has gold-standard HLA typing and high SNP density, thus using linkage disequilibrium patterns around SNPs and classical HLA alleles enables the inference of classical HLA alleles, amino acids and SNPs across the region based on the SNP data generated from Immunochip, an approach successfully used by a number of researchers 5 6 11 12. Post-imputation QC included removing variants with a MAF <0.01 and variants with an r 2 <0.8.…”

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

“…For T1D, the HLA-DQ8 allele (DQA1*03:01-DQB1*03:02) is present in 50% to 60% of all patients and provides an odds ratio for disease development of 6.5 to 11 (23)(24)(25). This is in stark contrast to HLA-DQ6 (DQB1*06:02), which confers dominant protection, with an odds ratio of 0.03 (25).…”