The Contribution of BMI to a young child’s risk of islet autoimmunity is dependent on HLA-DR4-DQ8 without HLA-DR3-DQ2

Objective Childhood obesity may impact the risk of islet autoimmunity (IA). The trajectory of BMI through childhood resembles the early peak incidence of first-appearing autoantibodies against insulin (IAA-first) but not GAD65 (GADA-first). We studied if a child’s BMI can impact the age-related risk of first appearing IA phenotypes. Research Design and Methods We identified 7,724 children at risk of IA with at least three BMI measurements in the Environmental Determinants of Diabetes in the Young (TEDDY) study. We modeled the risk of IAA-first, GADA-first, and IA overall, on a child’s BMI z-score and change in BMI during infancy (2 weeks to 1.5 years, n=7,724), early childhood (age 1.5-8.5 years, n=6,396), and puberty (age 8.5-15 years, n=4,732) using joint modeling of longitudinal BMI and time-to-event IA. Results An infant’s BMI z-score was not associated with IA risk before 18 months of age (n=185, HR 1.03, 95% CI [0.88, 1.19]). In contrast, a child’s BMI correlated with an increased risk of IA from 1.5 to 8.5 years (n=470, HR 1.20, 95% CI [1.04, 1.32]) and from 8.5 to 15 years (n =209, HR 1.27, 95% CI [1.09,1.49]). No interactions with first appearing IA phenotypes were observed. However, high BMI z-score (SD > 0.5) from age 9 months increased the risk of IA in early childhood specifically for children with HLA-DR4/4,8 and not with HLA-DR3/3,4 (HLA*BMI interaction, p<0.005). Conclusions The contribution of BMI to risk of IA during early childhood is dependent on HLA-DR-DQ genotype more so than first appearing IA phenotype.