Abstract
Aims/hypothesisAmong white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased.MethodsIn two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years.ResultsDR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes.Conclusions/interpretationHLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.Graphical abstract
Highlights
Type 1 diabetes is an autoimmune condition with a strong genetic predisposition
Within a type 1 diabetes cohort study (After Diabetes Diagnosis Research Support System-2 [ADDRESS-2]) and UK Biobank population cohort we evaluate the impact of the DR15-DQ6 genotype on type 1 diabetes risk throughout the first five decades of life
In two cohorts, we assessed the proportion of the type 1 diabetes population with DR15-DQ6 relative to control populations, comparing the proportion in those diagnosed in childhood and young adulthood to those diagnosed in older adulthood
Summary
Most of our understanding of the genetic architecture of type 1 diabetes is derived from case– control studies of children and adolescents [1]. Very few studies of DR15-DQ6 protection in type 1 diabetes have focused on adults in sufficient numbers, those diagnosed after the age of 30 years. Verifying this decreased DR15-DQ6 protection with increasing age of onset is essential prior to future mechanistic studies aiming to identify which specific genetic, immunological and environmental factors associated with being younger, enhance this protection
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