UC San Diego

Studies have shown that hepatic steatosis and fibrosis are heritable and have a shared gene\ effect with metabolic risk factors, but the heritability of the serum metabolites associated with NAFLD has not been assessed. The aim of this study was to investigate whether serum metabolites are heritable and if there are any shared gene effect with NAFLD. This study was a cross-sectional analysis of a prospective cohort of community-dwelling Twins and Family from southern California (156 subjects: 100 twins; 37 monozygotic, 13 dizygotic twin pairs; 56 sibling-sibling or parents-offspring). Hepatic steatosis was assessed using MRI-PDFF. Serum metabolite analysis was performed by Metabolon platform using UPLC-MS/MS and GC/MS. Serum metabolites associated with NAFLD were assessed using a Welch’s t-test and a sampling permutation by running 1,000 random selections of the dataset for each serum metabolite was performed to assess the familial effect. The association of serum metabolites with NAFLD was confirmed using generalized estimating equations (PROC GENMOD) to account for intrapair correlation within twinship. An ACE model was used to estimate the heritability of the serum metabolites and the shared gene effect (RG) between serum metabolites and NAFLD. Among 713 serum metabolites analyzed, 440 were heritable and of those, 57 had a shared gene effect with both hepatic steatosis and fibrosis; around 40% belonging to the amino acid superpathways. This study provides evidence that several serum metabolites associated with NAFLD are heritable and have shared gene effects suggesting that metabolites may be associated with the genetic susceptibility and pathogenesis of NAFLD.