Genetic association of T1D stratified by HLA DR3 and DR4 status reveals heterogeneity in pathways of progression to T1D

Abstract

BackgroundThere are substantial differences in the clinical presentation of type 1 diabetes (T1D) depending on the first-developing autoantibody, although the underlying mechanisms are poorly understood. The DR3-DQ2 (DR3) and DR4-DQ8 (DR4) haplotypes at the MHC locus closely associate with GAD and IAA as the first-developing autoantibody, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of T1D cases and controls. MethodsWe performed the first genome-wide association study of T1D stratified by DR3 and DR4 status using 9,091 T1D cases and 14,157 controls from multiple cohorts. We estimated heritability and genetic correlation between DR3-T1D and DR4-T1D, and with other immune and glycaemic phenotypes. We assessed heterogeneity in effects on T1D between DR3 and DR4 individuals at known T1D loci. We determined enrichment of T1D heritability in DR3 and DR4 among variants in cell type-specific cis-regulatory elements (cREs) and biological pathways, and annotated risk variants in cREs. ResultsWe observed only moderate genetic correlation between DR4- and DR3-T1D (rg=0.6), which was lower compared to stratifications based on age of onset and sex, and distinct patterns of genetic correlations with other autoimmune diseases. Among T1D-associated loci, the IL2 locus had significantly larger effect on T1D in DR4 while several other loci (TAGAP, KLRG1) had more nominal heterogeneity. There was stronger enrichment of DR4-T1D associated variants in T cell cREs and T cell-related pathways, while DR3-T1D associated variants were specifically enriched in mast cell cREs. We finally prioritized specific loci annotated in mast cells with stronger effects on T1D in DR3 individuals. ConclusionWe performed the first GWAS of T1D stratified by DR3 and DR4 status, which revealed heterogeneity in genetic risk and biological mechanisms dependent on high-risk HLA background.