Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

Abstract

the DPT-1 Study Group OBJECTIVE-The unfolding of type 1 diabetes involves a number of steps: defective immunological tolerance, priming of anti-islet autoimmunity, and destruction of insulin-producing ␤-cells. A number of genetic loci contribute to susceptibility to type 1 diabetes, but it is unclear which stages of the disease are influenced by the different loci. Here, we analyzed the frequency of type 1 diabetes-risk alleles among individuals from the Diabetes Prevention Trial-Type 1 (DPT-1) 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 one-third of which eventually progressed to diabetes. RESEARCH DESIGN AND METHODS-In this study, 708individuals randomized into DPT-1 were genotyped for 37 single nucleotide polymorphisms in diabetes susceptibility loci.RESULTS-Susceptibility alleles at loci expected to influence immunoregulation (PTPN22, CTLA4, and IL2RA) did not differ between progressors and nonprogressors 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 versus nonprogressors (DQB*0302, 42.6 vs. 34.7%, P ϭ 0.0047; DQB*0301, 8.6 vs. 14.3%, P ϭ 0.0026). Multivariate analysis of the factors contributing to progression demonstrated that initial titers of anti-insulin autoantibodies (IAAs) could account for some (P ϭ 0.0016) but not all of this effect on progression (P ϭ 0.00038 for the independent effect of the number of DQB*0302 alleles). The INS-23 genotype was most strongly associated with anti-IAAs (median IAA levels in TT individuals, 60 nU/ml; AT, 121; and AA, 192; P ϭ 0.000037) and only suggestively to the outcome of oral insulin administration.CONCLUSIONS-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.

Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families

“…In the T1DGC ASP families, homozygosity for the protective T allele at rs689 delayed diagnosis of T1D by 1.7 year and the frequency of the T allele was 0.02 higher in those diagnosed with T1D over 10 year than those diagnosed at 10 year or less. Combined with the previous findings,65,66 these results are consistent with the hypothesis that the T allele at rs689 delays the onset of T1D. However, the age-at-diagnosis effect, although associated at P = 0.001, is not observed in the JDRF/WT case series ( P = 0.32, unpublished data, n = 900 cases diagnosed >12 year).…”

“…Specifically, the age-at-diagnosis effect at INS requires further investigation. The rs689 (−23 Hph I) polymorphism was associated with anti-insulin autoantibodies ( P = 3.7 × 10 −5 ) 65,66. These auto-antibodies are rarely found in older onset T1D cases.…”

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…Other studies have not detected a significant association of the PTPN2 genotype with the development of islet autoantibodies [35,70,71]. No association of the PTPN2 rs1893217 risk genotype with progression to T1D has been detected in these studies or others [34,[70][71][72], although an interaction between the PTPN2 rs1893217 protective genotype and the vitamin D receptor SNP rs1544410 was associated with decreased risk of T1D in the DAISY cohort (p = 0.0004, HR = 0.24, 95% CI:0.11-0.53) [71]. Taken together, these studies indicate that the PTPN2 rs1893217 genotype alone does not appear to be a significant risk factor for the development of T1D, but PTPN2 may influence the development of islet autoimmunity and age at onset, suggesting a role for PTPN2 in disease initiation rather than progression.…”

Genetic-induced Variations in the GAD65 T-cell Repertoire Governs Efficacy of Anti-CD3/GAD65 Combination Therapy in New-onset Type 1 Diabetes

“…This is particularly relevant in humans where the diversity of HLA molecules can affect both the antigenic specificity of the T-cell repertoire and the ability to mount a T-cell response toward a particular antigen. T1D patients harbor a panel of HLA/MHC molecules43,44 which was suggested to affect therapeutic outcome 45. On the contrary, most preclinical studies using aAgs to induce tolerance were performed in a single animal model for T1D presenting a single MHC background.…”