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

Abstract

Aims/hypothesisA genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS53) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS53 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.MethodsWe 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 GRS53 was examined for association with metabolic traits in children by linear regressions using an additive genetic model.ResultsIn overweight/obese children and adolescents, the GRS53 associated with higher HOMA-IR (β = 0.109 ± 0.050 (SE); p = 2.73 × 10−2), fasting plasma glucose (β = 0.010 ± 0.005 mmol/l; p = 2.51 × 10−2) and systolic BP SD score (β = 0.026 ± 0.012; p = 3.32 × 10−2) as well as lower HDL-cholesterol (β = −0.008 ± 0.003 mmol/l; p = 1.23 × 10−3), total fat-mass percentage (β = −0.143 ± 0.054%; p = 9.15 × 10−3) and fat-mass percentage in the legs (β = −0.197 ± 0.055%; p = 4.09 × 10−4). In the population-based sample of children, the GRS53 only associated with lower HDL-cholesterol concentrations (β = −0.007 ± 0.003 mmol/l; p = 1.79 × 10−2).Conclusions/interpretationAn 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.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4640-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Interplay of an Obesity-Based Genetic Risk Score with Dietary and Endocrine Factors on Insulin Resistance

“…Consistently, an obesity GRS predicted the risk of IR in a Chinese children population [37]. Moreover, an adult-based GRS encompassing 53 SNPs was associated with the HOMA-IR index, metabolic syndrome traits, and altered fat distribution in a sample of Danish children and adolescents [38].…”

Abdominal adiposity and cardiometabolic risk factors in children and adolescents: a Mendelian randomization analysis

“…A previous study in the TDCOB cohort suggested that there may be differences in genetic influences on body fat distribution between children who are overweight/obese and those who are normal-weight (40). We performed analyses stratified by weight status to test whether the effect of the WHRadjBMI GRS on body fat distribution and cardiometabolic risk is modified by overweight/obesity.…”

<p><em>CHDH-PNPLA3</em> Gene–Gene Interactions Predict Insulin Resistance in Children with Obesity</p>

“…For example, results on 53 loci, in several genes including INSR, IRS1 and PIK3R1 genes, selected based on genome-wide analyses of fasting insulin adjusted for BMI, did not identify loci with a primary effect on higher adiposity and insulin resistance in a large study on adults. 38 However, a genetic score, computed from the same 53 loci, was associated with insulin resistance, in children with overweight or obesity, 45 suggesting that genomic approaches need to be integrative, and also envisaging gene-gene interaction effects. SNPs identified to be associated with NAFLD were not included in the 53 SNPs studied in relation to insulin resistance.…”