E167K Variant Research Articles

TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD.

Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury of HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell-membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.

PNPLA3 is one of the bridges between TM6SF2 E167K variant and MASLD.

PNPLA3 is one of the bridges between TM6SF2 E167K variant and MASLD.

Human induced pluripotent stem cell based hepatic-modeling of lipid metabolism associated TM6SF2 E167K variant.

TM6SF2 rs58542926 (E167K) is related to increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Conflicting mouse study results highlight the need for a human model to understand this mutation's impact. This study aims to create and characterize a reliable human in vitro model to mimic the effects of the TM6SF2-E167K mutation for future studies. We used gene editing on human human-induced pluripotent stem cells (iPSC) from a healthy individual to create cells with the TM6SF2-E167K mutation. After hepatocyte directed differentiation, we observed decreased TM6SF2 protein expression, increased intracellular lipid droplets and total cholesterol in addition to reduced VLDL secretion. Transcriptomics revealed upregulation of genes involved in lipid, fatty acid, and cholesterol transport, flux, and oxidation. Global lipidomics showed increased lipid classes associated with ER stress, mitochondrial dysfunction, apoptosis, and lipid metabolism. Additionally, the TM6SF2-E167K mutation conferred a pro-inflammatory phenotype with signs of mitochondria and ER stress. Importantly, by facilitating protein folding within the ER of hepatocytes carrying TM6SF2-E167K mutation, VLDL secretion and ER stress markers improved. Our findings indicate that induced hepatocytes generated from iPSCs carrying the TM6SF2-E167K recapitulate the effects observed in human hepatocytes from individuals with the TM6SF2 mutation. This study characterizes an in vitro model that can be used as a platform to identify potential clinical targets and highlights the therapeutic potential of targeting protein misfolding to alleviate ER stress and mitigate the detrimental effects of the TM6SF2-E167K mutation on hepatic lipid metabolism.

Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2

SummaryThe rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.

Perturbation of TM6SF2 Expression Alters Lipid Metabolism in a Human Liver Cell Line.

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

TM6SF2 E167K variant increases the severity of NAFLD in high fat diet-fed mice

TM6SF2 E167K variant increases the severity of NAFLD in high fat diet-fed mice

Differential Associations of Circulating MicroRNAs With Pathogenic Factors in NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease driven by genetic and environmental factors. MicroRNAs (miRNAs) serve as pleiotropic post‐transcriptional regulators of cellular pathways. Although several miRNAs have been associated with NAFLD and fibrosis, there are limited studies in humans examining their differential association with pathogenic factors or histological features of NAFLD. We examined the differential relationships of five of the best‐described circulating microRNAs (miR‐34a, miR‐122, miR‐191, miR‐192, and miR‐200a) with histological features and pathogenic factors of NAFLD. A cross‐sectional study was conducted to examine the relationship between relative levels of circulating microRNAs standardized by z‐scores and histological features of NAFLD, common NAFLD genetic polymorphisms, and insulin resistance measured by the enhanced lipoprotein insulin resistance index in 132 subjects with biopsy‐proven NAFLD. We found that miR‐34a, miR‐122, miR‐192, miR‐200a, but not miR‐191, strongly correlate with fibrosis in NAFLD by increases of 0.20 to 0.40 SD (P < 0.005) with each stage of fibrosis. In multivariate analysis, miR‐34a, miR‐122, and miR‐192 levels are independently associated with hepatic steatosis and fibrosis, but not lobular inflammation or ballooning degeneration, whereas miR‐200a is only associated with fibrosis. Among the four miRNAs, miR‐34a, miR‐122, and miR‐192 are associated with pathogenic factors of NAFLD, including insulin resistance measured by eLP‐IR, patatin‐like phospholipase domain containing 3 I148M, and transmembrane 6 superfamily 2 (TM6SF2) E167K polymorphisms. In contrast, miR‐200a is only associated with the TM6SF2 E167K variant. Finally, miR‐34a has the strongest predictive value for various stages of fibrosis, with C‐statistic approximates–combined predictive score for miRNAs. Conclusion: miR‐34a, miR‐122, miR‐192, and miR‐200a demonstrate strong associations with NAFLD severity by histology, but differential associations with pathogenic factors.

Interaction of TM6SF2 E167K and PNPLA3 I148M variants in NAFLD in northeast China

Introduction and aimThis study aimed to confirm the association of the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant with non-alcoholic fatty liver disease (NAFLD) and the degree of steatosis, as well as the additive effect of body mass index (BMI) or the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M and TM6SF2 E167K variants in NAFLD. Materials and methodsA total of 158 NAFLD patients and 158 matched controls were recruited. Steatosis was classified as mild, moderate and severe by FibroScan. Associations between the TM6SF2 E167K variant and NAFLD as well as clinical parameters were evaluated. ResultsAlthough the frequency of the T allele was low in the Chinese population (MAF=7.4%), there was still a significant association between the E167K variant and NAFLD (odds ratio=3.379, 95% confidence interval: 1.500–7.612, P=0.003). In particular, the TM6SF2 genotype was also associated with the degree of steatosis (P=0.023). The TM6SF2 variant was associated with increased alanine aminotransferase (ALT) but no other clinical parameters, such as aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lipids. Notably, we also found that an additive effect of the TM6SF2 E167K and PNPLA3 I148M variants in NAFLD. Furthermore, we did not identify an association between the TM6SF2 E167K variant and NAFLD in the non-obese population. ConclusionThe TM6SF2 E167K variant was associated with NAFLD in northeast China, and there was an interaction between the PNPLA3 I148M and TMS6F2 E167K variants in NAFLD.

Combining I148M and E167K variants to improve risk prediction for nonalcoholic fatty liver disease in Qingdao Han population, China

BackgroundPNPLA3 I148M variant and TM6SF2 E167K variant are recognized as the major genetic modifiers of nonalcoholic fatty liver disease (NAFLD). The present study sought to evaluate the potential additive effect of the two variants on the risk of NAFLD in Qingdao Han Population, China.MethodsWe genotyped PNPLA3 I148M variant and TM6SF2 E167K variant in a cohort of 512 unrelated NAFLD patients and 451 healthy controls by sequencing and polymerase chain reaction analysis. In addition, serum lipid profiles and liver enzymes were determined by standard clinical laboratory methods.ResultsThe minor allele frequencies were 45.48% for PNPLA3 148 locus G allele and 6.69% for TM6SF2 167 locus T allele. The PNPLA3 I148M variant was significantly associated with the risk of NAFLD in an additive model (CG, OR = 2.092, 95% CI: 1.551–2.820, P = 0.000; GG, OR = 4.566, 95% CI: 3.141–6.638, P = 0.000, respectively). And, our data suggested a strong link between the TM6SF2 E167K variant and the risk of NAFLD in a dominant model (CT + TT, OR = 2.327, 95% CI: 1.542–3.513, P = 0.000). In addition, the increasing of the number of risk alleles were associated with the risk of NAFLD (1 risk allele, OR = 1.687, P = 0.001; 2 risk alleles, OR = 4.326, P = 0.000; 3 risk alleles, OR = 6.018, P = 0.027, respectively).ConclusionsCombining the I148M and E167K variants in a manner of an additive effect could improve risk prediction for NAFLD in a Qingdao Han Population cohort.Trial registrationChinese Clinical Trial Register.gov: ChiCTR1800015426.

TM6SF2 E167K Variant Overexpression Promotes Expression of Inflammatory Cytokines in the HCC Cell Line HEPA 1-6.

Background and Aims: Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma (HCC), and E167K variant of the transmembrane 6 superfamily member 2 (TM6SF2) plays an important role in the progression of chronic liver diseases and HCC. The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8 in the HCC cell line HEPA 1-6.Methods: HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wild-type, or control plasmids. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8. A t-test was used for statistical analysis.Results: Compared with the control group and TM6SF2 overexpression group, the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group (p < 0.05). The relative mRNA expression of IL-8 in the TM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group (p < 0.05). No obvious differences were observed for the expression of TNF-α in each group. The expression of TNF-α, IL-2, IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results.Conclusions: In conclusion, the E167K variant of the TM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells, suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.

Lipoprotein metabolism in liver diseases.

The liver is the central hub of lipoprotein metabolism. A complex relationship exists between dyslipidemia and chronic liver diseases (CLDs). Recent advances in the genetics of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) exemplify the pivotal role of lipoprotein metabolism in the pathogenesis of CLD. We review these relationships in four quintessential forms of CLD: NAFLD, ALD, cholestatic liver disease and cirrhosis, with a focus on recent discoveries. An I148 M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) and an E167K variant in transmembrane 6 superfamily 2 (TM6SF2) are major genetic risk factors for the development and progression of NAFLD. These genetic variants also increase the risk of ALD. Both PNPLA3 and TM6SF2 are involved in the hepatic assembly of very low-density lipoprotein. The discovery of these two genetic variants highlights the risk of CLD when environmental factors are combined with functional modifications in the lipoprotein metabolism pathway. The relationship between CLD and lipoprotein metabolism is reciprocal. On the one hand, the progression of CLD impairs lipoprotein metabolism; on the other hand, modifications in lipoprotein metabolism can substantially increase the risk of CLD. These relationships are at play among the most common forms of CLD affecting a significant proportion of the population.

The Genetics of Clinical Liver Diseases: Insight into the TM6SF2 E167K Variant.

The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant (rs58542926) was identified by exome-wide association study as a nonsynonymous single nucleotide polymorphism associated with nonalcoholic fatty liver disease. The TM6SF2 E167K variant features a C-to-T substitution at nucleotide 499, encoding a glutamate with lysine change at codon 167 (E167K). TM6SF2 is markedly expressed in the liver, small intestine and kidney, and has been proposed as an important risk factor for diseases associated with lipid metabolism. Subsequently, multifunctional studies of the TM6SF2 E167K variant have been carried out in a spectrum of liver diseases, such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, fibrosis, cirrhosis, and viral hepatitis. This review summarizes the research status of the TM6SF2 E167K variant in different liver diseases and specific populations, and discusses the potential mechanisms of the TM6SF2 E167K variant’s role in the progression of various liver diseases.

The effect of the TM6SF2 E167K variant on liver steatosis and fibrosis in patients with chronic hepatitis C: a meta-analysis

The impact of Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant, which causes hepatocellular fat retention by altering lipoprotein secretion, on liver damage and metabolic traits in chronic hepatitis C patients is still debated. We performed a systematic review and meta-analysis to clarify this relationship. Four studies with a total of 4325 patients were included. The risk of histologically-determined advanced steatosis, fibrosis, and cirrhosis (but not of severe inflammation) were increased in carriers of the TM6SF2 variant (P < 0.05). Unlike the inconsistent association with steatosis severity, due to the confounding effect of infection by the genotype-3 hepatitis C virus, the TM6SF2 variant was robustly associated with advanced fibrosis (OR = 1.07; 95% confidence interval [CI] = 1.01–1.14) and in particular with cirrhosis (OR = 2.05; 95% CI = 1.39–3.02). Regarding metabolic features, individuals positive for the TM6SF2 variant exhibited 5.8–12.0% lower levels of circulating triglycerides and non-HDL cholesterol (P < 0.05). Carriers of the variant were leaner, but there was high heterogeneity across studies (I2 = 97.2%). No significant association was observed between the TM6SF2 variant and insulin resistance or hepatitis C viral load (both P > 0.05). In conclusion, the TM6SF2 E167K variant promotes the development of steatosis, fibrosis and cirrhosis in patients with chronic hepatitis C. Conversely, this variant reduces circulating atherogenic lipid fractions.

E167K polymorphism of TM6SF2 gene affects cell cycle of hepatocellular carcinoma cell HEPA 1-6

BackgroundSome studties reported that the polymorphism of TM6SF2 gene E167K affects the occurrence and the progression of hepatocytes carcinoma (hepatocellular, HCC). In oeder to investigate the effects of the polymorphism of TM6SF2 gene E167K in the pathogenesis of HCC, we explored its influence on the cell cycle in hepatocellular carcinoma cell HEPA1-6.MethodsHEPA 1–6 cells which could respectively overexpress TM6SF2 wild type and E167K variant were cultured and HEPA 1–6 cells with zero load plasmids were used as matched control. Flow cytometry was used to detect the cell cycles of these 3 type of HEPA 1–6 cells. Realtime fluores-cence quantitative PCR and western blot were used to analyzed the expression of regulatory factors (Cyclin D1、p53、P16、P27、P21 and Rb) of cell cycle. T-test was used in statistical analysis.ResultsCell cycle phase distribution was presented by the proportion of cells in each phases (%). Compared with the control group, the cell cycle phase distribution (G1 phase 57.36 ± 0.21%, G2/M phase 25.61 ± 0.36%,S phases 19.31 ± 0.25%) had no differences in wild type group (G1 phase 57.63 ± 0.28%, G2/M phase 25.77 ± 0.51%, S phases 19.54 ± 0.25%; P < 0.05). Between variant type group and wild type group,G1 phase was significantly decreased (variant type group G1 phase 36.26 ± 0.31%, P < 0.05),S phase and G2/M phase were increased(variant type group S phase 28.41 ± 0.31%, P < 0.05;G2/M phase 35.23 ± 0.14%, P < 0.05), respectively. Compared with control group,the relative expression of CyclinD1、P53 and Rb mRNA in variant type group was significantly upregulated (2.03 ± 0.01 VS 1.04 ± 0.06, 1.88 ± 0.05 VS 1.37 ± 0.03, 1.29 ± 0.06 VS 1.15 ± 0.03, P < 0.05) and P27 mRNA in variant type group was significantly downregulated (0.56 ± 0.02 VS 0.85 ± 0.05, P < 0.05).Compared with wild type group, the relative expression of CyclinD1、P53 and Rb mRNA in variant type group was significantly upregulated (wild type group 1.00 ± 0.00, 1.48 ± 0.09, 1.18 ± 0.01, P < 0.05) and P27 mRNA in variant type group was significantly downregulated (variant type group 0.82 ± 0.05,P < 0.05). There was no statistical significance between wild type group and control group (P > 0.05). P16 and P21 expression showed no statistical sigtfificance in any of these three groups (P > 0.05).ConclusionE167K polymorphism of TM6SF2 gene affects cell cycles of HEPA1–6 cells via up-regulating CyclinD1、P53 and Rb and down-regulating P27.

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

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.

Diagnosis of non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30U/l in men and ≈20U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by John Jones, DOI: 10.1007/s00125-016-3940-5 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).

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

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 = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 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 = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 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. 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).

Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review.

To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review. The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur. We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine. Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.

TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype.

AIMTo evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients.METHODSThe study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner’s scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4+ cells/mm3 = 505.5).RESULTSThe 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST (P = 0.02) and alanine aminotransferase (P = 0.02) and higher fibrosis score (3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCV-genotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed.CONCLUSIONIn HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.

TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver dysfunction worldwide, and its prevalence is highly associated with genetic susceptibility. The transmembrane 6 superfamily member 2 (TM6SF2) E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation, and its presence appears to be directly involved in the pathogenesis and development of NAFLD. Although this variant appears to be a novel powerful modifier in the development of NAFLD, whether it is associated with an increased risk of NAFLD-related liver fibrosis and hepatocellular carcinoma (HCC) remains to be determined. The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD, with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD. Additionally, the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.