Genetic and metabolic predictors of hepatic fat content in a cohort of Italian children with obesity

Abstract

Objectives: To comprehensively explore metabolic and genetic contributors to liver fat accumulation in overweight/obese children. Methods: Two hundred thirty Italian children with obesity were investigated for metabolic parameters and genotyped for PNPLA3, TM6SF2, GCKR, and MBOAT7 gene variants. Percentage hepatic fat content (HFF%) was measured by nuclear magnetic resonance. Results: HFF% was positively related with BMI, HOMA IR , metabolic syndrome, ALT, AST, γGT, and albumin. Carriers of [G] allele in PNPLA3, [T] allele in GCKR and [T] allele in TM6SF2 genes had significantly higher hepatic fat content than wild-type carriers. HFF% was explained for 8.7% by metabolic and for 16.1% by genetic factors and, a model including age, gender, BMI, HOMA IR , PNPLA3, GCKR, and TM6SF2 variants was the best predictor of HFF%, explaining 24.8% of its variation (P < 0.001). A weighted-genetic risk score combining PNPLA3, GCKR, and TM6SF2 risk alleles was associated with almost eightfold higher risk of NAFLD. Conclusions: Our data highlighted the predominant role of genetic factors in determining the amount of liver fat content in children with obesity.