CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, P = 0.002) and the CLEC16A AA genotype (rs12708716, P = 0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (P = 0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (P = 0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups. The impact of HLA-DQ2/DQ8, the main genetic risk factor for accelerating progression from 1 to multiple autoantibodies, largely depended on CTLA4 status in the Belgian cohort.

Automated summary

The HLA region is the major genetic risk determinant of Type 1 diabetes. Non-HLA loci, such as INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA, may also contribute to the genetic risk by impacting the progression of asymptomatic autoimmunity. In this study, the researchers investigated the relationship between SNPs in these susceptibility loci and the progression from single to multiple autoantibody positivity, as well as the development of clinical diabetes. They found that certain genotypes in CTLA4 and CLEC16A were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were limited to specific conditions. The interaction between CTLA4 and HLA-DQ2/DQ8 was found to override the effect of HLA-DQ2/DQ8 alone. The study also showed that SH2B3 genotype was protective for HLA-DQ8 positive subjects, while CTLA4 genotype was a minor independent risk factor for progression towards clinical diabetes. The findings suggest that non-HLA polymorphisms impact the progression of islet autoimmunity in specific ways and may have implications for risk assessment and prevention trials in at-risk groups.