Genetic Basis for Nonalcoholic Fatty Liver Disease: The role of MBOAT7-p.Gly17Glu-missense variant

SILVIA SOOKOIAN; CARLA GAZZI; MARTIN E GARAYCOECHEA; CARLOS J. PIROLA; DIEGO FLICHMAN; GUSTAVO CASTAÑO

Boston, MA

Congreso; Liver Meeting 2016; 2016

AASLD

Background and Aims: Current knowledge on the genetic basis of nonalcoholic fatty liver disease (NAFLD) demonstrates that variants not just contributing to the disease susceptibility but severity are located in genes that regulate lipid metabolism. Specifically, the rs738409 in PNPLA3 has been consistently associated with NAFLD severity and fibrosis stage across different populations in adults and children. However, associations with further discovered variants located in lipid-related loci, including the recently identified rs641738 (p.Gly17Glu) in MBOAT7 (Membrane Bound O-Acyltransferase Domain Containing 7) were not consistently replicated across ethnic groups; MBOAT7 encodes for a member of the membrane-bound O-acyltransferases family that has specificity for arachidonoyl-CoA as an acyl donor. Notably, reported results showed genotype frequencies deviated from Hardy-Weinberg equilibrium (HWE). Here, we explored whether the MBOAT7-rs641738 is associated with the genetic risk of NAFLD and the disease severity in a case-control study of patients with NAFLD proven by liver biopsy.Methods: Our study included 634 individuals (372 patients with NAFLD and 262 healthy controls); genotyping was performed by a Taqman assay. Our sample had 96% power for the additive genetic model. To account for possible population stratification, we used a collection of 13 SNPs at different loci that were analyzed with the Structure program and which showed similar clustering for cases and controls.. Results: In our population, genotype frequencies in controls (n= CC: 84, CT: 137, TT: 41) and patients (CC: 134, CT: 178, TT: 60) were in HWE; minor allele frequency was 40.8 %. The rs641738 variant was neither associated with increased susceptibility to NAFLD (Cochran-Armitage test for trend chi-sq. = 0.397, P = 0.529) or the disease severity (p = 0.61). However, in univariate analysis we observed a significant association with circulating triglycerides (TG) (p=0.004). The rs641738 was not associated either with glucose metabolism, HOMA-index, total, HDL, LDL-cholesterol or other MetS components. Conclusion: While the role of rs641738 in NAFLD seems not to be conclusive, the variant may be associated with TG levels and so, it might indirectly regulate intermediate steps of fatty acid (polyunsaturated fatty acids-PUFA and PUFA-containing TG) biosynthesis. Still unexplored gene-diet interactions may explain disproportionately impact of variants on NAFLD among different ethnic groups. Not replicated observations among different populations indeed may result from disparities in the dietary composition.