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

Diabetologia. 2003 May;46(5):712-20. doi: 10.1007/s00125-003-1082-z. Epub 2003 May 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / blood
  • Autoimmunity / genetics
  • Child
  • Child, Preschool
  • DNA / blood
  • DNA / genetics
  • Diabetes Mellitus, Type 1 / epidemiology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 2 / genetics*
  • European Continental Ancestry Group
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Germany
  • HLA-DQ Antigens / genetics*
  • HLA-DR Antigens / genetics*
  • Humans
  • Infant
  • Insulin / genetics*
  • Life Tables
  • Major Histocompatibility Complex / genetics*
  • Minisatellite Repeats / genetics*
  • Risk Assessment
  • Risk Factors


  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • Insulin
  • DNA