Phenotypic characterization of seven genetic variants associated with non-alcoholic fatty liver disease

Abstract

Background: Previous studies have identified several genetic variants associated with non-alcoholic fatty liver disease (NAFDL) (PNPLA3, TM6SF2, MBOAT7, GCKR, SAMM50), and two genetic variants protective of NAFLD (PPP1R3B, HSD17B13). Objective: To characterize the metabolic pathways associated with genetic variants related to the risk of NAFDL in a large population-based METSIM study cohort. Methods: We genotyped the genetic variants by TaqMan or Sequenom, and measured metabolites by mass spectrometry (Metabolon, USA). We associated the genetic variants with 857 metabolites in 5,181 participants of the METSIM study. P<5.8 x 10-5 was considered as statistically significant given the 857 metabolites included in statistical analyses. Results: PNPLA3 variant was significantly associated only with one glycerophospholipid [1-myristoyl-2-arachidonoyl-glycerophosphocholine (14:0/20:4)] and retinol, whereas a TM6SF2 variant was associated with several glycerolipids and glycerophospholipids, a MBOAT7 variant with several glycerophosphoinositols, and a GCKR variant with several glycerolipids, glycerophospholipids, and amino acids. PPP1R3B variant was associated with amino acids, fatty acids, and hydroxy acids. SAMM50 and HSD17B13 variants were associated only with one metabolite. All seven genetic variants were associated almost entirely with different individual metabolites among lipids, amino acids, and other metabolites. Conclusion: We found that metabolite profiles were very specific for each genetic variant, suggesting multiple pathophysiological etiologies for NAFLD. Our study offers novel information about the metabolic pathways associated with the risk of NAFLD.