Polymorphisms within HLA gene loci are strongly associated with susceptibility to autoimmune disorders; however, it is not clear how genetic variations in these loci confer a disease risk. Here, we devised a cell-surface MHC expression assay to detect allelic differences in the intrinsic stability of HLA-DQ proteins. We found extreme variation in cell-surface MHC density among HLA-DQ alleles, indicating a dynamic allelic hierarchy in the intrinsic stability of HLA-DQ proteins. Using the case-control data for type 1 diabetes (T1D) for the Swedish and Japanese populations, we determined that T1D risk–associated HLA-DQ haplotypes, which also increase risk for autoimmune endocrinopathies and other autoimmune disorders, encode unstable proteins, whereas the T1D–protective haplotypes encode the most stable HLA-DQ proteins. Among the amino acid variants of HLA-DQ, alterations in 47α, the residue that is located on the outside of the peptide-binding groove and acts as a key stability regulator, showed strong association with T1D. Evolutionary analysis suggested that 47α variants have been the target of positive diversifying selection. Our study demonstrates a steep allelic hierarchy in the intrinsic stability of HLA-DQ that is associated with T1D risk and protection, suggesting that HLA instability mediates the development of autoimmune disorders.
Authors
Hiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, Katsushi Tokunaga
(A–D) Associations between the amino acid variants in HLA-DQA1 (A and B) and -DQB1 (C and D) and susceptibility to T1D in the Swedish (A and C) and Japanese populations (B and D). The ORs (circles) and the lowest P value (triangle) at each site (χ2 test). ORs and P values for the variants that are distinct between DQ2/3/4 and DQ5/6 are shaded in orange. ORs for 2α and 199α in the Swedish population are not presented. See Supplemental Tables 6 and 7 for the association tables.