V A Horton

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 with islet cell antibodies and with specific “high-risk” HLA-DRB1 and HLA-DQB1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can have islet-related antibodies, but the genotypic associations at different 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) or glutamic acid decarboxylase antibodies (GADA) or both by age is associated with different DRB1 and DQB1 genotypes. Methods. The antibodies to islet cells and those to glutamic acid decarboxylase were measured in 1712 white Caucasian diabetic subjects at diagnosis of 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-risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of high-risk alleles in diabetic patients was expressed relative to the prevalence of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in both the diabetic patients and in 200 non-diabetic control subjects. The prevalence of ICA or GADA or both in patients with different HLA 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 45–54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1-fold over-representation, 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 patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10 % in those aged 55–65 years and expected 3 % prevalence. Conversely, only 14 % of those aged 25–34 years with antibodies had non-DR3/non-DR4, compared with 35 % in those aged 55–65 years. There was thus pronounced age heterogeneity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1 genotypes in the multivariate model for requiring insulin therapy by 6 years of follow-up. Conclusion/hypothesis. The age of presentation of Type I diabetes in adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years. [Diabetologia (1999) 42: 608–616]

An association analysis of the HLA gene region in latent autoimmune diabetes in adults

Aims/hypothesisPathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis.Materials and methodsPatients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR.ResultsAs in type 1 diabetes mellitus, DRB1*0301_DQB1*0201 (odds ratio [OR] = 3.08, 95% CI 2.32–4.12, p = 1.2 × 10−16) and DRB1*0401_DQB1*0302 (OR = 2.57, 95% CI 1.80–3.73, p = 4.5 × 10−8) were the main susceptibility haplotypes in LADA, and DRB1*1501_DQB1*0602 was protective (OR = 0.21, 95% CI 0.13–0.34, p = 4.2 × 10−13). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (OR = 1.79, 95% CI 1.35–2.38, p = 2.7 × 10−5) whereas DRB1*0403 was protective (OR = 0.37, 95% CI 0.13–0.97, p = 0.033). The highest-risk genotypes were DRB1*0301/DRB1*0401 and DQB1*0201/DQB1*0302 (OR = 5.14, 95% CI 2.68–10.69, p = 1.3 × 10−8; and OR = 6.88, 95% CI 3.54–14.68, p = 1.2 × 10−11, respectively). These genotypes and those containing DRB1*0401 and DQB1*0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1*1501 and DQB1*0602 associated with an older age at diagnosis.Conclusions/interpretationPatterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.

The Variable Number of Tandem Repeats Upstream of the Insulin Gene Is a Susceptibility Locus for Latent Autoimmune Diabetes in Adults

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at −23HphI (odds ratio [OR] 0.42 [95% CI 0.31–0.58], P = 2.4 × 10−8), A allele at +1,404Fnu4HI (0.50 [0.36–0.70], P = 3.2 × 10−5), and C allele at +3,580MspI (0.55 [0.35–0.85], P = 0.0046). As with type 1 diabetes, the −23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA.

UKPDS 21: Low Prevalence of the Mitochondrial Transfer RNA gene (tRNA Leu(UUR)) Mutation at Position 3243bp in UK Caucasian Type 2 Diabetic Patients

Some patients with Type 2 (non‐insulin‐dependent) diabetes mellitus possess a mitochondrial mutation in the tRNALeu(UUR) gene at position 3243 bp. These subjects show a maternal mode of inheritance and often have hearing defects. In French and Japanese populations, this mutation may be present in 1–3 % of subjects with a family history of diabetes. We assessed the prevalence of this mutation in newly diagnosed diabetic subjects in the UK white Caucasian population. The 3243 bp mutation was not detected in 500 randomly selected Type 2 diabetic subjects, 50 gestational diabetic subjects, and members of a MODY pedigree. Two of 748 (0.27 %) Type 2 diabetic subjects with a family history of diabetes were found to possess the mutation. These subjects had an early age of diagnosis (M 38 years; F 36 years) and were non‐obese. The male patient showed evidence of markedly impaired beta‐cell function and deafness, while the female was not deaf, had approximately 50 % of normal pancreatic function and responded well to diet. The mutation in the tRNALeu(UUR) gene probably occurs in only approximately 0.1–0.2 % of white Caucasian Type 2 diabetic patients in the UK.