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

Abstract

A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10−6, n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents –2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a –28% increase in serum ALT.

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

“…These findings suggest that carriage of the TM6SF2 T risk allele is associated with decreased hepatic gene and protein expression, leading to a loss of function similar to the mutant PNPLA3 variant. In turn, the wild type TM6SF2 protein has been associated with increased serum VLDL levels and an elevated cardiovascular risk [32], but less liver injury [33]. Whether and how there may be cross-talk between TM6SF2 and signaling pathways pertinent for HCC development beyond mere intracellular lipid accumulation and lipotoxicity remains to be elucidated.…”

In vitro analysis of hepatic stellate cell activation influenced by transmembrane 6 superfamily 2 polymorphism

“…The number of patients is increasing worldwide, accompanied by recent upward trends in obesity, westernized high-fat oral intake, gut dysbiosis, inadequate exercise, and comorbid metabolic disorders like diabetes mellitus (2,24). To identify factors associated with NAFLD, clinical studies have concluded that the prevalence, prognosis, and progression or severity of disease is significantly associated with SNPs in PNPLA3 (rs738409) and TM6SF2 (rs58542926) (4,5,11,25,26). Several studies have shown that the rs738409SNP in PNPLA3 causes a loss-of-function amino acid substitution (I148M) in PNPLA3 that affects regulation of lipid droplets in human hepatocytes and retinol metabolism in human HSCs, resulting in positive modulation of HSC activation (27,28).…”

Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology

“…TM6SF2, of which rs58542926 C/T (E167K) was initially associated with liver fat accumulation and aminotransferase levels in a large GWAS study 21 and further replicated in subsequent studies, 21,[33][34][35] encodes for a protein involved in lipid metabolism. 12 Diverse areas of molecular knowledge gained on this gene/protein are presented in Figure 2.…”