GLP-1R gene polymorphisms and metabolic traits during childhood and adolescence: The EPOCH study

Abstract Aims/Hypothesis This is the first study to examine the association between variants of the glucagon-like-peptide-1 receptor gene (GLP-1R) and metabolic characteristics among youth. We explored separate associations of three GLP-1R polymorphisms (rs10305420, rs6923761, and rs1042044) with BMI trajectories and markers of glucose-insulin homeostasis. Methods Mixed models examined associations between GLP-1R polymorphisms and trajectories of BMI. Linear models examined associations of GLP-1R polymorphisms with glucose and insulin concentrations across OGTT, insulin sensitivity (HOMA2-IR), insulin secretion (insulinogenic index and HOMA2-%B), and beta cell function (oral disposition index). Results Rs10305420 and rs6923761, but not rs1042044, were associated with growth and metabolic characteristics in early life. Rs6923761 genotype GG was associated with faster BMI growth velocity, when compared to carriers of the minor allele (difference in velocity [95% CI]: 0.16 kg/m2/year [0.07, 0.24] at age 10), which led to significantly higher average BMI by age 16 (average difference [95% CI]: 1.29 kg/m2 [0.22, 2.37]). Rs10305420 CC and rs6923761 GG genotypes had higher HOMA2-IR (β[95% CI]: 1.19%[1.06, 1.32] and 1.13%[1.01, 1.26], respectively) compared to minor allele carriers. Rs10305420 CC had higher HOMA2-%B (β[95% CI]: 1.09%[1.01, 1.17]), and higher stimulated insulin secretion at 30-minutes (β[95% CI]: 27.62 uIU/mL [3.00, 25.24]) and 120-minutes (β[95% CI]: 18.94 uIU/mL [1.04, 36.84), when compared to carriers of the minor allele. Conclusions GLP-1R polymorphisms were associated with faster BMI growth across development, and lower estimated insulin sensitivity and higher compensatory insulin secretion during adolescence. GLP-1R polymorphisms should be considered in future pediatric studies of genetic susceptibility for obesity and diabetes.