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.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

HLA-A∗24 carrier status and autoantibody surges posttransplantation associate with poor functional outcome in recipients of an islet allograft

OBJECTIVE We investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid β- cell loss in pre-type 1 diabetes, associate with poor functional outcome in islet allograft recipients. RESEARCH DESIGN AND METHODS Forty- one patients received ≥2.3 million β-cells/kg body wt in one to two intraportal implantations. Outcome after 6-18 months was assessed by C-peptide (random and stimulated), insulin dose, and HbA1c .RESULTS Patients carrying HLA-A∗24-positive or experiencing a significant autoantibody surge within 6 months after the first transplantation (n 5 19) had lower C-peptide levels (P ≤ 0.003) and higher insulin needs (P < 0.001) despite higher HbA1c levels (P ≤ 0.018). They became less often insulin independent (16% vs. 68%, P 5 0.002) and remained less often C- peptide positive (47% vs. 100%, P < 0.001) than recipients lacking both risk factors. HLA-A∗24 positivity or an autoantibody surge predicted insulin dependence (P 5 0.007). CONCLUSIONS HLA-A∗24 and early autoantibody surge after islet implantation associate with poor functional graft outcome.SCOPUS: ar.jinfo:eu-repo/semantics/publishe