An Adult-based Insulin Resistance Genetic Risk Score Associates with Insulin Resistance, Metabolic Traits and Altered Fat Distribution in Danish Children and Adolescents Who Are Overweight or Obese

Aims/hypothesis: A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.

Methods: We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS was examined for association with metabolic traits in children by linear regressions using an additive genetic model.

Results: In overweight/obese children and adolescents, the GRS associated with higher HOMA-IR (β = 0.109 ± 0.050 (SE); p = 2.73 × 10), fasting plasma glucose (β = 0.010 ± 0.005 mmol/l; p = 2.51 × 10) and systolic BP SD score (β = 0.026 ± 0.012; p = 3.32 × 10) as well as lower HDL-cholesterol (β = -0.008 ± 0.003 mmol/l; p = 1.23 × 10), total fat-mass percentage (β = -0.143 ± 0.054%; p = 9.15 × 10) and fat-mass percentage in the legs (β = -0.197 ± 0.055%; p = 4.09 × 10). In the population-based sample of children, the GRS only associated with lower HDL-cholesterol concentrations (β = -0.007 ± 0.003 mmol/l; p = 1.79 × 10).

Conclusions/interpretation: An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.