DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life

Nicholas J Thomas, John M Dennis, Seth A Sharp, Akaal Kaur, Shivani Misra, Helen C Walkey, Desmond G Johnston, Nick S Oliver, William A Hagopian, Michael N Weedon, Kashyap A Patel, Richard A Oram, Nicholas J Thomas, John M Dennis, Seth A Sharp, Akaal Kaur, Shivani Misra, Helen C Walkey, Desmond G Johnston, Nick S Oliver, William A Hagopian, Michael N Weedon, Kashyap A Patel, Richard A Oram

Abstract

Aims/hypothesis: Among 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.

Methods: In 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.

Results: DR15-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/interpretation: HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.

Keywords: Adult onset type 1 diabetes; DR15-DQ6; Genetic predisposition; Genetic protection; Genetic resistance; HLA; Type 1 diabetes.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Comparison of risk HLA genotype vs protective HLA genotype loge ORs for developing type 1 diabetes defined by clinical diagnosis and autoantibody positivity within the first five decades of life within the ADDRESS-2 study. The highest risk compound heterozygote and homozygote risk HLA genotypes are shown in Table 2 for comparison. Bars represent 95% CIs
Fig. 2
Fig. 2
The difference in incidence of diabetes per 100,000 person-years in different HLA genotypes relative to a neutral HLA genotype within the UK Biobank. Bars represent 95% CIs
Fig. 3
Fig. 3
Mean non-HLA T1DGRS plotted against mean T2DGRS within individuals with insulin-treated diabetes in UK Biobank diagnosed at aged 31–50 years stratified by HLA genotype group. Individuals with one or two copies of DR15-DQ and those with type 1 diabetes risk-increasing genotypes (presence of DR3 and/or DR4-DQ8) are shown. Cohorts with type 1 diabetes, type 2 diabetes and controls without diabetes are plotted for reference. Bars represent 95% CIs

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