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. 2025 Dec 1;48(12):2103-2110.
doi: 10.2337/dc25-1198.

The Contribution of BMI to a Young Child's Risk of Islet Autoimmunity Is Dependent on HLA-DR4-DQ8 Without HLA-DR3-DQ2

Jaakko J Koskenniemi  1 , Joanna L Clasen  1 , Lu You  1 , Hemang M Parikh  1 , Kendra Vehik  1 , Jimin Yang  1 , Ulla Uusitalo  1 , Riitta Veijola  2   3 , Michael J Haller  4 , Anette G Ziegler  5   6 , Marian J Rewers  7 , William A Hagopian  8 , Beena Akolkar  9 , Åke Lernmark  10 , Jorma Toppari  11   12 , Helena Elding Larsson  10   13 , Jeffrey P Krischer  1 , Kristian F Lynch  1 ; TEDDY Study Group*
Collaborators, Affiliations

The Contribution of BMI to a Young Child's Risk of Islet Autoimmunity Is Dependent on HLA-DR4-DQ8 Without HLA-DR3-DQ2

Jaakko J Koskenniemi et al. Diabetes Care. .

Abstract

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 whether 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 for 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 (age 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, hazard ratio [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 of age (n = 470, HR 1.20 [95% CI 1.04, 1.32]) and from 8.5 to 15 years of age (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 or HLA-DR4/8 and not with HLA-DR3/3 or HLA-DR3/4 (HLA ∗ BMI interaction, P < 0.005).

Conclusions: The contribution of BMI to risk of IA during early childhood is dependent on the HLA-DR-DQ genotype more so than the first-appearing IA phenotype.

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Conflict of interest statement

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
A: The mean curve of BMI, 95% reference range (shaded area), and example curves with high and low child infancy BMI z scores. B: The incidence of IA during childhood in the TEDDY study.
Figure 2
Figure 2
Cumulative incidence of IA during early childhood (1.5–8.5 years) according to BMI z score (SD) at age 9 months (orange dashed line, >0.5; green solid line, ≤0.5), stratified by HLA haplogenotype.
See this image and copyright information in PMC

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