<em>Objective</em>: 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. <em>Research Design and Methods</em>: 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, <i>in utero</i> exposure to maternal
diabetes, and genetic principal components. We also evaluated effect
modification by BMI z-score,<i> in utero </i>exposure to maternal diabetes and
ethnicity. <em>Results</em>: 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 <i>in utero</i> exposure to maternal diabetes increased the effect
of the GRS on glucose levels. <em>Conclusions</em>: 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.
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RE: “ADDITIVE AND MULTIPLICATIVE INTERACTIONS BETWEEN GENETIC RISK SCORE AND FAMILY HISTORY AND LIFESTYLE IN RELATION TO RISK OF TYPE 2 DIABETES”