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
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 children 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 performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3).
In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P=0.007), more pronounced in boys (P=3x10-7) than girls (P=0.07), and with increasing IGF-1 (P=0.002) and IGFBP-3 (P=0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were respectively associated with lower IGF-1 concentrations at age 12 months (P=0.003) and greater skinfold thickness at age 24 months (P=0.003).
The variable associations of DR4, DR3 and DQ8 alleles with growth measures and IGF-1 levels in infants from the general population could explain the heterogeneous 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.