Background and Aim: Several genetic variants associating with hepatic fat content in adults have been identified in genome-wide association studies. Their effects in children remain unclear. This study aimed to test the effect of genetic variants known to associate with hepatic fat in adults, individually and combined as a genetic risk score (GRS), on cardiometabolic traits, and to investigate the predictive ability of the GRS for hepatic steatosis in children.
Methods: Children with overweight/obesity from an obesity clinic cohort (n = 1,843, median age 11.7 years, body mass index standard deviation score [BMI SDS] 2.85, 45.2% male) and a population-based cohort (n = 2,271, median age 11.6 years, BMI SDS 0.26, 40.1% male) were included. Anthropometrics and biochemical parameters were measured in both cohorts. Liver fat content (LFC) was measured by magnetic resonance spectroscopy in 539 individuals. We calculated a weighted GRS based on eight genetic variants known to associate with hepatic fat content in adults. Associations of individual genetic variants and the GRS with cardiometabolic traits were tested using multiple linear and logistic regression models. Receiver operating characteristic (ROC) curve analysis was performed on models based on risk factors for hepatic steatosis, defined as hepatic fat ≥ 5 %, and area under the curve (AUC) was calculated to evaluate model performance.
Results: Variants in PNPLA3, TM6SF2, GPAM, and GCKR were significantly associated with higher LFC (P< 0.01) and with distinct patterns of circulating lipids. The GRS was associated with higher LFC and alanine transaminase (ALT), as well as lower LDL-cholesterol and triglycerides in both cohorts. The GRS was not associated with adiposity or other metabolic traits. The GRS was associated with higher prevalence of hepatic steatosis (odds ratio [OR] per 1-unit GRS-increase: 2.18, P=1E-8), and with lower prevalence of dyslipidaemia (OR 0.90, P=0.02). A prediction model for hepatic steatosis including GRS alone, yielded cross-validated AUC of 0.76 (95% CI 0.69-0.83). The addition of the GRS to a model containing clinical risk factors for hepatic steatosis (BMI SDS, ALT, homeostatic model assessment of insulin resistance [HOMA-IR]) increased AUC slightly from 0.87 (95% CI 0.82-0.92) to 0.89 (95% CI 0.84-0.94).
Conclusion: The adult-based GRS for hepatic fat associated with LFC, liver enzymes, and lipid profiles, but was not associated with adiposity and other metabolic traits in children. The GRS could serve as a clinical risk predictor of hepatic steatosis and be used in early prevention.
15 Sep 2022 - 17 Sep 2022