IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity

Abstract

Aim/hypothesis. Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/insulin (INS) 5′ variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. Methods. Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. Results. Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. Conclusion/Interpretation. Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk. [Diabetologia (2003) 46:712-720]

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

“…The association of IAA with the risk INS genotype is supported by observations made in two other recent studies on patients with newly diagnosed type 1 diabetes and on first-degree relatives [7,22]. Recently, a more preserved beta cell function in recent-onset cases was found in individuals with the INS VNTR class III allele compared with those carrying class I alleles [37].…”

“…It has also been suggested that the INS locus confers increased disease risk only in subjects with moderate-risk HLA genotypes [20]. However, recent studies have suggested that the INS polymorphism could modify progression to clinical disease among individuals with both high-risk and low-risk HLA genotypes [21][22][23]. Data on the effect of the CTLA4 gene region on beta cell autoimmunity are similarly ambiguous.…”

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

“…HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were typed using PCR-amplified DNA and non-radioactive sequence-specific oligonucleotide probes as described previously [21,22].…”

A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes

“…INS gene polymorphisms are also associated with type 1 diabetes risk and have hazard ratios that exceed those of the 12 genes examined in the current study. 2,4,11 We therefore added the INS genotype to the 12 SNPs and performed ROC analysis on the 8191 possible combinations. Remarkably, 1117 combinations had an AUC with Po0.0001 and 117 combinations had an AUC with Po10 À 5 (Supplementary Figure 3).…”

“…The number of children who were successfully typed are listed in Supplementary Table 1. Complete successful typing for HLA and all 12 additional type 1 diabetes genes were obtained for 1290 children. INS gene polymorphisms were obtained on 1382 children as previously described, 11 and including 1288 of those with HLA and all 12 gene SNP data.…”