Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes

Abstract

A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P 5 0.02) but not different in cohorts with CHC (n 5 2023) and chronic hepatitis B (n 5 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio 5 1.39, 95% confidence interval 1.04-1.87, and odds ratio 5 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection. Conclusion: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (HEPATOLOGY 2016;64:34-46)

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

“…1. Characteristics of studies included in the meta-analysis of liver enzymes in NAFLD1216192021222324252627 ( n  = 11) are shown in Table 1, while those included in the meta-analysis of patients with viral hepatitis15161718 ( n  = 4) are summarized in Table 2.…”

“…Furthermore, conflicting and non-replicated results found in some151617 but not all of the studies18 that the E167K variant could be associated with steatosis in patients with the hepatitis C virus (HCV) as well; nevertheless, the associations with liver enzymes could not be demonstrated in patients with chronic hepatitis.…”

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

“…Also, alcoholics carrying the susceptible TM6SF2 genotype seem to be at risk of liver cirrhosis (14). Recently, Eslam et al (22) analyzed the effects of this variant on metabolic traits and liver status in a cohort of 3,260 individuals, among which a total of 502 presented with NAFLD. In this study, variant TM6SF2 was overrepresented in patients with NAFLD, among whom presence of the minor TM6SF2 allele was associated with increased fibrosis and lower serum triglycerides.…”

Host – hepatitis C viral interactions: The role of genetics

“…More recently, the role of virus-host interactions in relation to the PNPLA3 polymorphism has been explored. This indicated an association with hepatic steatosis, especially in patients infected with HCV genotype non-3, and as well to fibrosis progression [100,101].…”

“…Other studies have linked the same variant to fibrosis progression and the risk of HCC in NAFLD [103]. With regard to a role for this variant in modulating liver histology in viral liver disease, it has been reported to be associated with steatosis in CHC, while any effect on fibrosis was modest in CHC [101,104].…”