Genetic Risk Score for Type 2 Diabetes and Traits Related to Glucose-Insulin Homeostasis in Youth: The Exploring Perinatal Outcomes Among Children (EPOCH) Study

Objective: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. Research Design and Methods: We used data from 356 youth (mean age 16.7 years, 50% female) in the EPOCH cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms (SNPs) associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-hour glucose, homeostasis model of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, body mass index (BMI) z-score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z-score, in utero exposure to maternal diabetes and ethnicity. Results: Higher weighted GRS was associated with lower oral disposition index (b=-0.11; 95% CI: -0.19, -0.02) and insulinogenic index (b=-0.08; 95% CI: -0.17, -0.001), but not with fasting glucose (b=0.01; 95% CI: -0.01, 0.02), 2-hour glucose (b=0.03; 95% CI: -0.0004, 0.06), or HOMA-IR (b=0.02; 95% CI: -0.04, 0.07). BMI z-score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. Conclusions: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk for T2D.