Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43)

Aims/hypothesis. Juvenile-onset, insulin-dependent diabetes is associated w ith islet cell antibodies and with specific "high-risk" HLA-DRB1 and HLA-DQ B1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellit us can have islet-related antibodies, but the genotypic associations at dif ferent ages of onset have not been evaluated. Our aim was to determine (i) the prevalence of DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different ages from 25 to 65 years compared with the general population, and (ii) whether the presence of islet cell antibodies (ICA) o r glutamic acid decarboxylase antibodies (GADA) or both by age is associate d with different DRB1 and DQB1 genotypes. Methods. The antibodies to islet cells and those to glutamic acid decarboxy lase were measured in 1712 white Caucasian diabetic subjects at diagnosis o f diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the high -risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high-r isk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalenc e of high-risk alleles in diabetic patients was expressed relative to the p revalence of low-risk alleles, non-DR3/non-DR4. that provided a reference d enominator in both the diabetic patients and in 200 non-diabetic control su bjects. The prevalence of ICA or GADA or both in patients with different HL A genotypes was assessed in those diagnosed in four age groups, 25-34 years , 35-44 years, 45-54 years and 55-65 years. Results. In Type II diabetic patients presenting at ages 25-34, 35-44 and 4 5-54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 0.5-fold, 2.9-fold, 2.1-fold over-rep resentation, respectively (p<0.0001, < 0.01, < 0.05) but this was not found in those aged 55-65 years old. In the group aged 25-34 years, 32 % of pati ents with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 1 0% in those aged 55-65 years and expected 3% prevalence. Conversely, only 1 4% of those aged 25-34 pears with antibodies had non-DR3/non-DR4, compared with 35% in those aged 55-65 years. There was thus pronounced age heterogen eity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies di splaced DRB1 or DQB1 genotypes in the multivariate model for requiring insu lin therapy by 6 years of follow-up. Conclusion/hypothesis. The age of presentation of Type I diabetes in adulth ood was in part dependent on the DRB1/DQB1 genotype. Isfet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DR B1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years.