The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study Diabetes Care 2021;44:1852–1859 | https://doi.org/10.2337/dc20-2820 Antigoni Eleftheriou, 1 Clive J. Petry, 1 Ieuan A. Hughes, 1 Ken K. Ong, 1–3 and David B. Dunger 1,3 OBJECTIVE This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort. RESEARCH DESIGN AND METHODS The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 chil- dren had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4, rs2187668 for DR3, and rs7454108 for DQ8. Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were per- formed under additive genetic effects to test for associations between HLA poly- morphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3). RESULTS In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P 5 0.007), which was more pronounced in boys (P 5 3 Â 10 À7 ) than girls (P 5 0.07), and was also associated with increasing IGF-I (P 5 0.002) and IGFBP-3 (P 5 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were associ- ated with lower IGF-I concentrations at age 12 months (P 5 0.003) and greater skinfold thickness at age 24 months (P 5 0.003), respectively. CONCLUSIONS The variable associations of DR4, DR3, and DQ8 alleles with growth measures and IGF-I levels in infants from the general population could explain the heteroge- neous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk. 1 Department of Paediatrics, University of Cambridge, Cambridge, U.K. 2 MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K. 3 Institute of Metabolic Science, University of Cambridge, Cambridge, U.K. Corresponding author: David B. Dunger, dbd25@ cam.ac.uk Received 18 November 2020 and accepted 5 May 2021 This article contains supplementary material online at https://doi.org/10.2337/figshare.14574210. © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/content/license. CARDIOVASCULAR AND METABOLIC RISK 1852 Diabetes Care Volume 44, August 2021 Downloaded from http://diabetesjournals.org/care/article-pdf/44/8/1852/633287/dc202820.pdf by guest on 27 May 2023