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).
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 beta-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.


METHODS
In this study, 708 individuals 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 = 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 (IAAs) 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-IAAs (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.


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.
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Vincent
V
Butty
Christopher
C
Campbell
Diane
D
Mathis
Christophe
C
Benoist
D015703:Antigens, CD / Q000235:genetics; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018450:Disease Progression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007328:Insulin / Q000008:administration & dosage* / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D015999:Multivariate Analysis; D010919:Placebos; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012307:Risk Factors; D016896:Treatment Outcome
D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007004:Hypoglycemic Agents; C508017:IL2RA protein, human; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D010919:Placebos; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22