GLP-1R Polymorphisms Modify the Relationship Between Exposure to Gestational Diabetes and Offspring BMI Growth: The EPOCH Study

Harrall KK, et al. Diabetes Care. 2025 Jul 1;48(7):1280-1287. PMID: 40443355; PMCID: PMC12178627.

This study investigates whether common polymorphisms in the glucagon-like peptide-1 receptor gene (GLP-1R) modify the relationship between in utero exposure to gestational diabetes mellitus (GDM) and offspring BMI growth and glucose-insulin homeostasis. Using data from 464 participants in the EPOCH cohort, researchers examined three GLP-1R variants (rs10305420, rs6923761, rs1042044) and their interaction with GDM exposure on longitudinal BMI trajectories and metabolic markers. Key findings include:

• All three GLP-1R polymorphisms significantly modified the association between GDM exposure and BMI growth from early childhood through adolescence.
  • For rs10305420 and rs1042044, children with at least one minor allele and GDM exposure had significantly higher BMI trajectories than those without GDM exposure.
  • For rs6923761, the effect was most pronounced in major allele homozygotes (GG), where GDM exposure was associated with the highest BMI across childhood and adolescence.
• None of the GLP-1R variants modified the association between GDM exposure and surrogate markers of insulin sensitivity or secretion (e.g., HOMA2-IR, HOMA2-%B, insulinogenic index, oral disposition index) during adolescence.
• None of the GLP-1R variants modified the association between GDM exposure and surrogate markers of insulin sensitivity or secretion (e.g., HOMA2-IR, HOMA2-%B, insulinogenic index, oral disposition index) during adolescence.

These findings suggest that GLP-1R polymorphisms may help identify children at heightened risk for accelerated BMI gain following GDM exposure. While GDM is a known risk factor for childhood obesity, genetic susceptibility—particularly involving GLP-1R—may explain interindividual variability in outcomes. However, the lack of interaction with glucose-insulin markers suggests that BMI and metabolic dysregulation may be influenced by distinct mechanisms.