Both genetic and non-genetic factors are important in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to identify novel metabolites and pathways associated with NAFLD by including both genetic and non-genetic factors in statistical analyses. We genotyped six genetic variants in the PNPLA3, TM6SF2, MBOAT7, GCKR, PPP1R3B, and HSD17B13 genes reported to be associated with NAFLD. Non-targeted metabolomic profiling was performed from plasma samples. We applied a previously validated fatty liver index to identify participants with NAFLD. First, we associated the six genetic variants with 1098 metabolites in 2 339 men without NAFLD to determine the effects of the genetic variants on metabolites, and then in 2 535 men with NAFLD to determine the joint effects of genetic variants and non-genetic factors on metabolites. We identified several novel metabolites and metabolic pathways, especially for PNPLA3, GCKR, and PPP1R38 variants relevant to the pathophysiology of NAFLD. Importantly, we showed that each genetic variant for NAFLD had a specific metabolite signature. The plasma metabolite signature was unique for each genetic variant, suggesting that several metabolites and different pathways are involved in the risk of NAFLD. The FLI index reliably identifies metabolites for NAFLD in large population-based studies.
Keywords: genetic variants; metabolomics; non-alcoholic fatty liver disease.