Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes

Abstract

Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations with genetic variation map to classical HLA class II genes. Because of its genetic complexity, the HLA region has been under-represented in genome-wide association studies, having potentially hindered the identification of relevant associations underlying the etiology of the disease. Here, we performed a comprehensive HLA-wide genetic association analysis of type 1 diabetes including multi-allelic and rare variants. We used high-density whole-exome sequencing data of the HLA region in the large UK Biobank dataset to apply gene-based association tests with a carefully defined type 1 diabetes phenotype (97 cases and 48,700 controls). Exon-based and single-variant association tests were used to complement the analysis. We replicated the known association of type 1 diabetes with the classical HLA-DQ gene. Tailoring the analysis toward rare variants, we additionally identified the lysine methyl transferase EHMT2 as associated. Deeper insight into genetic variation associated with disease as presented and discussed in detail here can help unraveling mechanistic details of the etiology of type 1 diabetes. More specifically, we hypothesize that genetic variation in EHMT2 could impact autoimmunity in type 1 diabetes development.