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

Abstract

Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear.

Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization.

Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y.

Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal.

Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Trial registration: ClinicalTrials.gov NCT00928473.

Keywords: ALSPAC; Mendelian randomization; abdominal adiposity; cardiometabolic risk; cardiovascular disease risk; children; meta-analysis; waist-to-hip ratio.

FIGURE 1

Linear regression analysis to test the association of the WHR_adjBMI-increasing GRS with cardiometabolic variables in all children and adolescents (n = 9895). The results are expressed as β values (95% CIs) of the inverse normally transformed traits, showing their association with the WHR_adjBMI-increasing allele of the GRS. All analyses are adjusted for age, puberty, and the first 3 genome-wide principal components. The effects were pooled using fixed-effects meta-analyses. The numerical values for βs, SEs, P values, and sample sizes are presented in Supplemental Table 2. *P values < 0.05. BMI-SDS, BMI SD score; GRS, genetic risk score; WHR_adjBMI, waist-to-hip ratio–adjusted BMI; β in SD/allele, effect on the inverse normally transformed trait per allele increase.

FIGURE 2

Mendelian randomization analysis to test the causal effect of childhood abdominal adiposity on LDL cholesterol, HDL cholesterol, and triglycerides. The figure shows associations of the WHR_adjBMI genetic risk score with LDL cholesterol, HDL cholesterol, triglycerides, and observational WHR_adjBMI, as well as the associations of the observational WHR_adjBMI with LDL cholesterol, HDL cholesterol, and triglycerides. The results of the instrumental variable analysis are obtained from 2-staged least-squares regression analyses. β values are expressed as units of SD of the inverse normally transformed traits. P values < 0.05 are shown in bold. WHR_adjBMI, waist-to-hip ratio–adjusted BMI; β in SD/allele, effect on the inverse normally transformed trait per allele increase.