The roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: A meta‐analysis of 24,147 subjects

Abstract

Background Some genetic association studies tried to investigate potential associations of transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms with chronic liver disease. However, the results of these studies were not consistent. Thus, we performed the present meta‐analysis to explore associations between TM6SF2 polymorphisms and chronic liver disease in a larger pooled population. Methods Systematic literature research of PubMed, Web of Science, Embase, and CNKI was performed to identify eligible studies for pooled analyses. I2 statistics were employed to assess between‐study heterogeneities. If I2 was greater than 50%, random‐effect models (REMs) would be used to pool the data. Otherwise, fixed‐effect models (FEMs) would be applied for synthetic analyses. Results Totally 28 studies were included for analyses (13,137 cases and 11,010 controls). The pooled analyses showed that rs58542926 polymorphism was significantly associated with chronic liver disease in overall population (dominant model: p < 0.0001, OR = 0.70, 95% CI = 0.64–0.76, I2 = 47%; recessive model: p < 0.0001, OR = 2.94, 95% CI = 2.05–4.20, I2 = 0%; over‐dominant model: p < 0.0001, OR = 1.34, 95% CI = 1.23–1.47, I2 = 0%; allele model: p < 0.0001, OR = 0.68, 95% CI = 0.63–0.73, I2 = 47%), and these significant findings were further confirmed in both Asians and Caucasians. Stratified analyses by type of disease revealed similar positive results in hepatocellular carcinoma (HCC), cirrhosis, alcoholic liver disease (ALD) and NAFLD (Nonalcoholic fatty liver disease), but not in chronic hepatitis B infection (CHB) and chronic hepatitis C infection (CHC). Conclusions These results suggested that TM6SF2 rs58542926 could be used to identify individuals at higher susceptibility to chronic liver disease, especially for HCC, cirrhosis, ALD, and NAFLD.

Genes Potentially Associated with Familial Hypercholesterolemia

“…The rs10490626 polymorphism correlates with total cholesterol and LDL-C levels according to a genome-wide association study and meta-analysis [120]. The rs58542926 polymorphic variant of the TM6SF2 gene is used to identify individuals with a higher susceptibility to chronic liver diseases, especially hepatocellular carcinoma, cirrhosis, alcoholic liver disease, and nonalcoholic fatty liver disease [121,122]. LIMA1 encodes a negative regulator of cholesterol absorption, and its mutations lead to a decrease in the LIMA1 protein level [123].…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Though the specific role of Tm6sf2 gene is not yet known, these data point towards its contribution to NAFLD development, and hence, its translational applicability. Remarkably, a recent meta-analysis showed that rs58542926 polymorphism significantly associated with chronic liver disease in the overall population [73]. These novel data pointed towards the diagnostic ability of TM6SF2-polymorphism to identify individuals at higher risk for developing NAFLD, cirrhosis, and HCC, as well as alcohol-dependent liver disease [73].…”

“…Similarly, hepatic knockdown of transmembrane 6 superfamily member 2 (Tm6sf2), a gene responsible for regulating hepatic lipid metabolism and associated with increased susceptibility to human NAFLD [73], resulted in increased hepatic fat content and decreased VLDL secretion [74]. Though the specific role of Tm6sf2 gene is not yet known, these data point towards its contribution to NAFLD development, and hence, its translational applicability.…”

Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease

“…For instance, Sookoian et al [88], did not find any associations between the TM6SF2 mutation and circulating transaminases, necroinflammation and fibrosis possibly due to the low frequency of the rs58542926 polymorphism and lack of statistical power. Conversely, a meta-analysis of 24, 147 individuals affected by heterogeneous chronic liver disorders associated the TM6SF2 rs58542926 genotype with higher susceptibility to develop MAFLD, ALD, cirrhosis, and HCC than viral hepatitis [93]. In alcohol abusers affected by alcohol-related cirrhosis, the presence of the rs58542926 C > T variant represented an additional risk factor to develop HCC [94].…”