Dataset Information

TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis.

ABSTRACT:

Background and aims

Findings about the associations between transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 and nonalcoholic fatty liver disease have not been consistently replicated, particularly in steatosis and fibrosis. The present study aimed to investigate the associations between the rs58542926T allele and the spectrum of NAFLD and its related metabolic phenotypes.

Methods

Systematic literature research was performed to analyse the associations between rs58542926 and the spectrum of NAFLD and its related metabolic phenotypes. A random effects meta-analysis with a dominant genetic model was applied.

Results

Data from 123,800 individuals across 44 studies were included in the current meta-analysis.rs58542926 T allele was associated with an increased risk of NAFLD in both adults (OR=1.62; 95% CI: 1.40, 1.86) and children (OR=2.87; 95% CI: 1.85, 4.46). Children had a stronger association with NAFLD (P=0.01). rs58542926 T allele was also positively associated with steatosis progression (mean difference=0.22; 95% CI: 0.05, 0.39) and fibrosis stage (OR=1.50; 95% CI: 1.20, 1.88) in adults. The TM6SF2 rs58542926 T allele was positively associated with ALT in both adults and children (both P<0.01) and only with higher AST in adults (P<0.01). The rs58542926 T allele was negatively associated with serum total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TGs) in both adults and children (all P<0.01).The serum level of TG was much lower in adults than in children (P<0.01).

Conclusion

TM6SF2 rs58542926 is involved in the entire spectrum of NAFLD and its related metabolic phenotype, and differences in serum lipid levels were observed between adults and children.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288163.

SUBMITTER: Li XY

PROVIDER: S-EPMC9637980 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis.

Li Xue-Ying XY Liu Zheng Z Li Li L Wang Hai-Jun HJ Wang Hui H

Frontiers in endocrinology 20221024

<h4>Background and aims</h4>Findings about the associations between transmembrane 6 superfamily member 2 (<i>TM6SF2</i>) rs58542926 and nonalcoholic fatty liver disease have not been consistently replicated, particularly in steatosis and fibrosis. The present study aimed to investigate the associations between the rs58542926T allele and the spectrum of NAFLD and its related metabolic phenotypes.<h4>Methods</h4>Systematic literature research was performed to analyse the associations between rs585 ...[more]

PMID: 36353245

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Project description:Background and aimsHuman transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD.Approach and resultsTwo independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels.ConclusionsLiver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.

Project description:Background and Objectives: Metabolic-dysfunction-associated steatotic liver disease or MASLD is the main cause of chronic liver diseases in children, and it is estimated to affect 35% of children living with obesity. This study aimed to identify metabolic phenotypes associated with two advanced stages of MASLD (hepatic steatosis and hepatic steatosis plus fibrosis) in Mexican children with obesity. Materials and Methods: This is a cross-sectional analysis derived from a randomized clinical trial conducted in children and adolescents with obesity aged 8 to 16 years. Anthropometric and biochemical data were measured, and targeted metabolomic analyses were carried out using mass spectrometry. Liver steatosis and fibrosis were estimated using transient elastography (Fibroscan® Echosens, Paris, France). Three groups were studied: a non-MASLD group, an MASLD group, and a group for MASLD + fibrosis. A partial least squares discriminant analysis (PLS-DA) was performed to identify the discrimination between the study groups and to visualize the differences between their heatmaps; also, Variable Importance Projection (VIP) plots were graphed. A VIP score of >1.5 was considered to establish the importance of metabolites and biochemical parameters that characterized each group. Logistic regression models were constructed considering VIP scores of >1.5, and the receiver operating characteristic (ROC) curves were estimated to evaluate different combinations of variables. Results: The metabolic MASLD phenotype was associated with increased concentrations of ALT and decreased arginine, glycine, and acylcarnitine (AC) AC5:1, while MASLD + fibrosis, an advanced stage of MASLD, was associated with a phenotype characterized by increased concentrations of ALT, proline, and alanine and a decreased Matsuda Index. Conclusions: The metabolic MASLD phenotype changes as this metabolic dysfunction progresses. Understanding metabolic disturbances in MASLD would allow for early identification and the development of intervention strategies focused on limiting the progression of liver damage in children and adolescents.

Project description:LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561-570).

Dataset Information

TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis.

Background and aims

Methods

Results

Conclusion

Systematic review registration

Publications

TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis.

Similar Datasets

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