Human leukocyte antigen genotype, body mass index status, and young-adult-onset type 1 diabetes

Obesity is increasingly recognized as a risk factor not only for type 2 diabetes but also for type 1 diabetes. We assessed its interaction with genetic susceptibility in the risk for adult-onset type 1 diabetes. We conducted a population-based retrospective cohort study of 604,968 Israeli adolescents (aged 16–19 years; 44% females) evaluated between 1996 and 2016 and followed for incident type 1 diabetes. Human leukocyte antigen (HLA) genotyping was performed at baseline; high-risk HLA was defined by the presence of predetermined class I or II risk alleles. Body mass index (BMI) was measured at adolescence and categorized using the 85th percentile as a cutoff. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Interaction between HLA risk and BMI was assessed. During 4.8 million person-years of follow-up (mean, 7.9 years), 151 participants developed type 1 diabetes. A significant additive interaction between HLA risk and BMI was observed (relative excess risk due to interaction, 4.79; 95% CI, 1.16–8.41; P = 0.010). Compared to adolescents with standard-risk HLA and lean BMI, adjusted HRs for type 1 diabetes were 0.56 (95% CI, 0.13–2.40) for standard-risk HLA with high BMI, 4.59 (95% CI, 2.77–7.60) for high-risk HLA with lean BMI, and 8.94 (95% CI, 5.07–15.75) for high-risk HLA with high BMI. Participants with high-risk alleles in both class I and II loci and high BMI had a 25.77-fold increased risk (95% CI, 13.27–50.05). HLA genotypes and adolescent BMI interact to substantially increase the risk of adult-onset type 1 diabetes. These findings may inform population risk stratification and screening strategies.