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Impact of diabetes susceptibility loci on progression from pre-diabetes to diabetes in at-risk individuals of the DPT1 trial

Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215

Objective: The unfolding of type-1 diabetes (T1D) involves a number of steps: defective immunological tolerance, priming of anti-islet autoimmunity, destruction of insulin-producing β-cells. A number of genetic loci contribute to susceptibility to T1D, but it is unclear which stages of the disease are influenced by the different loci. Here, we analyzed the frequency of T1D-risk alleles among individuals from the DPT1 clinical trial, which tested a preventive effect of insulin in at-risk relatives of diabetic individuals, all of which presented with autoimmune manifestations, but only 1/3 of which eventually progressed to diabetes.

Design: 708 individuals randomized into DPT1 were genotyped for 37 SNPs in diabetes susceptibility loci.

Results: Susceptibility alleles at loci expected to influence immunoregulation (PTPN22, CTLA4, IL2RA) did not differ between progressor and non-progressors, but were elevated in both groups relative to general population frequencies, as was the INS promoter variant. In contrast, HLA DQB1*0302 and DQB1*0301 differed significantly in progressors vs. non-progressors (DQB*0302: 42.6% vs. 34.7, p=0.0047; DQB*0301: 8.6% vs. 14.3%, p=0.0026). Multivariate analysis of the factors contributing to progression demonstrated that initial titers of anti-insulin autoantibodies (IAA) could account for some (p=0.0016), but not all of this effect on progression (p=0.00038 for the independent effect of the number of DQB*0302 alleles). The INS-23 genotype was most strongly associated with anti-insulin autoantibodies (median IAA levels in TT individuals 60 nU/ml, AT 121 and AA 192, p=0.000037), and only suggestively to the outcome of oral insulin administration.

Conclusion: With the exception of HLA, most susceptibility loci tested condition the risk of autoimmunity rather than the risk of failed immunoregulation that results in islet destruction. Future clinical trials might consider genotyping INS-23 in addition to HLA alleles as disease/treatment response modifier.

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