Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

Abstract

The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings atPTPN22,INS, andNRP1.Novel findings included associations withERBB3,UBASH3A,PTPN2, andFUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations withPTPN2,CD226, andPTPN22were replicated, and a novel association withSTAT4was observed. Analyzing the appearance of autoantibodies in endotypes, thePTPN22association was specific for IAA-first. In the progression phase,STAT4was specific for IAA-first andERBB3to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.