Apolipoprotein A5 gene polymorphisms are associated withnon-alcoholic fatty liver disease

Background: Several studies have reported that apolipoprotein A5(APOA5) is involved in the development of non-alcoholic fatty liver disease(NAFLD). However, no research has been performed regarding the association between APOA5 polymorphisms and the risk of NAFLD. This study aimed to explore the association between APOA5 gene polymorphisms and NAFLD in a Chinese Han population.Methods: Genotypes of the SNPs(rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 in 232 NAFLD patients and 188 healthy controls were determined using polymerase chain reaction(PCR)analysis. Clinical characteristics were measured using biochemical methods.Results: The five single nucleotide polymorphisms(SNPs)(rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 showed no significant association with NAFLD(P > 0.05). The rs10750097 with G allele showed a higher serum level of alkaline phosphatase(ALP) compared with C allele in overall series and NAFLD patients(P < 0.05). The rs1263173(A/A) carriers showed a higher level of glucose compared to the non-carriers in overall series(P < 0.05). The rs17120035(T/T) carriers showed a lower plasma TG level in overall series and NAFLD patients(P < 0.05), and the rs662799(G/G) carriers showed higher levels of plasma triglyceride(TG), ALP, and lower level of high-density lipoprotein(HDL) compared to non-carriers in NAFLD patients(P < 0.05). No significant difference were observed on the clinic parameters of APOA5 rs3135507(T/T) carriers in both group of overall series and NAFLD patients(P > 0.05).Conclusions: The five SNPs(rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 gene are not associated with the risk of NAFLD in the Chinese Han population. The genotypes of rs10750097(G/G), rs1263173(A/A), rs17120035(T/T), and rs662799(G/G) performed a significant effect on clinic characteristics in overall series and NAFLD patients, indicating that these polymorphisms may be associated with NAFLD.

Noninvasive Quantitative Detection Methods of Liver Fat Content in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease(NAFLD)ranges from simple steatosis to NAFLD-related liver cirrhosis and is a main cause of chronic liver diseases.Patients with nonalcoholic steatohe-patitis and fibrosis are at a great risk of the progression to cirrhosis or hepatocellular carcinoma,both of which are tightly associated with liver-related mortality.Liver biopsy is still the gold standard for the diagnosis of NAFLD,but some defects,such as serious complications,sampling error and variability in histologic evaluation among pathologists,remain problematic.Therefore,noninvasive,repeatable and accurate diagnostic methods are urgently needed.Ultrasonography is a well-established and lower-cost imaging technique for the diagnosis of hepatic steatosis,especially suitable for population census,but limited by its low sensitivity to diagnose mild steatosis and being highly operator-dependent.Computed tomography also lacks the sensitivity to detect mild steatosis and small changes in fat content,and presents a potential radiation hazard.Controlled attenuation parameter based on the FibroScan?technology is a promising tool for noninvasive semiquantita-tive assessment of liver fat content,but the accuracy rate de-pends on the operator's expertise and is affected by age,width of the intercostal space,skin capsular distance and body mass index.Magnetic resonance imaging and magnetic resonance spectroscopy are regarded as the most accurate quantitative methods for measuring liver fat content in clinical practice,especially for longitudinal follow up of NAFLD patients.In this review,we mainly introduce the current imaging methods that are in use for evaluation of liver fat content and we discuss the advantages and disadvantages of each method.

Association of GCKR Gene Polymorphisms with the Risk of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in a Chinese Northern Han Population

Background and Aims: Accumulated studies have eval-uated the effects of glucokinase regulatory protein(GCKR)gene polymorphisms on the risk of nonalcoholic fatty liver disease(NAFLD)and coronary artery disease(CAD),but the association of GCKR polymorphisms with the risk of NAFLD and CAD in the Chinese Han population have remained un-clear.The aim of this study was to investigate the association between GCKR gene polymorphisms(rs780094 and rs1260326)and the risk of NAFLD and CAD in NAFLD patients in a Chinese Northern Han population.Methods: GCKR rs780094 and rs1260326 gene polymorphisms were geno-typed by polymerase chain reaction sequencing for B-type ultrasonography-proven NAFLD patients with(n = 82)or without(n = 142)CAD,and in healthy controls(n = 152).Serum lipid profiles'levels were determined using biochemi-cal methods.Statistical analyses were conducted using SPSS 22.0 statistical software.Results: As the results showed,sig-nificant differences in the serum lipid profiles existed between each group.No significant differences were observed in the distributions of genotypes and alleles of GCKR rs780094 and rs1260326 in each group.The GCKR rs780094 T and rs1260326 T allele carriers possessed decreased body mass index value,and serum fasting plasma glucose and TG levels in the overall subjects,respectively.In addition,the GCKR rs780094 T allele carriers possessed decreased serum fasting plasma glucose level in the controls and NAFLD+CAD patients.Conclusions: GCKR rs780094 and rs1260326 poly-morphisms were found to be not associated with the risk of NAFLD nor of CAD in NAFLD patients in this Chinese Northern Han population.GCKR rs780094 T and rs1260326 T alleles could affect the body mass index value and serum fasting plasma glucose and triglyceride levels.

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 as-sociation study as a nonsynonymous single nucleotide poly-morphism 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 im-portant risk factor for diseases associated with lipid metabo-lism.Subsequently,multifunctional studies of the TM6SF2 E167K variant have been carried out in a spectrum of liver dis-eases,such as nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,fibrosis,cirrhosis,and viral hepatitis.This re-view 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 var-iant's role in the progression of various liver diseases.

Systematic Review and Meta-analysis of Circulating Fetuin-A Levels in Nonalcoholic Fatty Liver Disease

Background and Aims:Accumulated studies have reported the key role of circulating fetuin-A in the development and progression of nonalcoholic fatty liver disease(NAFLD)but the results have not been consistent.In this study,we performed a systematic review and meta-analysis to explore the relationship between circulating fetuin-A level and the development and classification of NAFLD.Methods:The PubMed,EMBASE,and Cochrane Library databases were searched to obtain the potentially relevant studies up to May 2020.Standardized mean differences(SMD)and 95%confidence intervals of circulating fetuin-A levels were extracted and summarized.Sensitivity,subgroup analysis and meta-regression analysis were performed to investigate the potential heterogeneity.Association of circulating fetuin-A level with classification of NAFLD was also reviewed.Results:A total of 17 studies were included,composed of 1,755 NAFLD patients and 2,010 healthy controls.Meta-analysis results showed that NAFLD patients had higher circulating fetuin-A level(SMD=0.43,95%confidence interval[CI]:0.22-0.63,p<0.001)than controls.Subgroup analysis indicated that circulating fetuin-A level was markedly increased in adult NAFLD patients(SMD=0.48,95%CI:0.24-0.72,p<0.001)and not in pediatric/adolescent patients compared to controls.Circulating fetuin-A level was markedly increased in ultrasound-proven NAFLD pediatric/adolescent patients(SMD=0.42,95%CI:0.12-0.72,p=0.007),other than in the liver biopsy-proven NAFLD pediatric/adolescent patients.Body mass index might be the influencing factor to the heterogeneity in adult patients.Circulating fetuin-A level was not associated with the classification of NAFL vs.nonalcoholic steatohepatitis(NASH).Whether the circulating fetuin-A level was associated with the development of fibrosis remains controversial.

Association between NAFLD and Risk of Colorectal Adenoma in Chinese Han Population

Background and Aims:Colorectal cancer is associated with non-alcoholic fatty liver disease(NAFLD)and other metabolic syndromes,such as obesity,abnormal blood glucose,and dyslipidemia.The relationship of NAFLD and colorectal adenoma,which is the precursor of colorectal cancer,is worthy of discussion.The aim of this study was to investigate the association between colorectal adenoma and NAFLD,colorectal adenoma and metabolic syndrome in a Chinese Han population.Methods:This retrospective study analyzed the relationship between NAFLD and colorectal adenoma in 1089 patients in Qingdao municipal hospital.Subjects were divided into a colorectal adenoma group(n=267)and a control group(n=822).NAFLD and the controlled attenuation parameter(CAP)value were determined by abdominal ultrasound and FibroScan.Results:Patients with NAFLD in the colorectal adenoma group and the control group represented 142 cases(53.2%)and 360 cases(43.8%),respectively.The mean CAP value in the colorectal adenoma group was significantly higher than that in the control group.The values of body mass index,triglyceride,high-density lipoprotein cholesterol,aspartate aminotransferase,fasting plasma glucose,and uric acid were also significantly higher in the colorectal adenoma group than in the control group.Multifactor logistic regression analysis showed that the sex,NAFLD,CAP,body mass index,triglyceride,aspartate aminotransferase,and fasting plasma glucose were significant risk factors for colorectal adenoma.Besides,NAFLD and CAP value were significant risk factors for colorectal adenoma in males but not in females.Conclusions:NAFLD and metabolic syndrome were tightly associated with the risk of colorectal adenoma in this Chinese Han population.The effect of NAFLD on colorectal adenoma was prominent in males rather than in females.

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-cα,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 wildtype,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 theTM6SF2 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-αin 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 theTM6SF2 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.

Tenofovir Alafenamide Fumarate,Tenofovir Disoproxil Fumarate and Entecavir:Which is the Most Effective Drug for Chronic Hepatitis B?A Systematic Review and Meta-analysis

Background and Aims:The therapeutic effect of tenofovir alafenamide fumarate(TAF),tenofovir disoproxil fumarate(TDF)and entecavir(ETV)on chronic hepatitis B(CHB)patients remains inconsistent.The aim of this study was to explore the differences in virological responses to TAF,TDF and ETV in patients with CHB.Methods:Literature searches were conducted of the PubMed,EMBASE,and the Cochrane Library databases to identify randomized controlled trials and observational studies published up to July 21,2020.Statistical comparisons of virological response between TDF,ETV,and TAF were carried out with pooled odds ratio(OR)values.Results:The virological response in TDF-treated CHB patients was notably superior to that of the ETV-treated CHB patients after 12-weeks[OR=1.12,95%confidence interval(CI):0.89–1.41],24-weeks(OR=1.33,95%CI:1.11–1.61),48-weeks(OR=1.62,95%CI:1.16–2.25),72-weeks(OR=1.43,95%CI:0.78–2.62),and 96-weeks(OR=1.56,95%CI:0.87–2.81)treatment.No significant difference was observed for the virological responses in CHB patients after 48-weeks treatment with TAF or TDF.The virological response in TDF+ETV-treated CHB patients was superior to that of TDF-treated CHB patients after 24-weeks,48-weeks(OR=1.54,95%CI:1.17–2.02),96-weeks,and 144-weeks.Conclusions:The virological response in TDF-treated CHB patients was superior to that in ETV-treated CHB patients,but there was no significant difference between TAF and TDF.In addition,the therapeutic effect of TDF+ETV was superior to TDF alone.

Association of TCF7L2 rs7903146 Gene Polymorphism with the Risk of NAFLD and CAD in the Chinese Han Population

Background and Aims:Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that TCF7L2 rs7903146 was related to the risk of developing NAFLD but the conclusions are not consistent and no related study has been conducted in Chinese populations. The aim of this study was to investigate the association be-tween TCF7L2 rs7903146 and the risk of developing NAFLD and CAD in a Chinese Han population. Methods: TCF7L2 rs7903146 genotypes were measured by the MALDI-TOF-MS from 143 NAFLD patients, 159 CAD patients, 131 NAFLD+ CAD patients, and 212 healthy controls. The demographic data and serum lipid profiles of all subjects were collected. The distributions of genotype and allele frequency in each group were also tested. Logistic regression was used to inves-tigate the risk of TCF7L2 rs7903146 with NAFLD and CAD. All statistical analyses were conducted using SPSS 23.0. Results: There were no significant differences in the distri-butions of TCF7L2 rs7903146 genotype and allele frequency in each of the two groups, and the TCF7L2 rs7903146 CT+TT genotype did not increase the risk of developing NAFLD, CAD, and NAFLD+CAD. Except for body mass index in the control group, the differences of clinical parameters between the TCF7L2 rs7903146 T allele carriers and non-carriers in each group were not significant. In the non-obese group, the TCF7L2 rs7903146 CT+TT genotype was a protective factor for the development of NAFLD in the non-obese subjects (odds ratio=0.359, 95% confidence interval: 0.134-0.961, p = 0.041). Conclusions: TCF7L2 rs7903146 was not associated with the risk of developing NAFLD, CAD, and NAFLD + CAD in the Chinese Han population. In the non-obese population, the TCF7L2 rs7903146 CT + TT genotype was a protective factor against the development of NAFLD.

Serum Resistin Levels in Adult Patients with Nonalcoholic Fatty Liver Disease:A Systematic Review and Meta-analysis

Background and Aims:Previous studies reported that serum resistin levels were remarkably changed in patients with nonalcoholic fatty liver disease(NAFLD)but the conclusions were inconsistent.The aim of this study was to investigate accurate serum resistin levels in adult patients with NAFLD.Methods:A complete literature research was conducted in the PubMed,Embase,and Cochrane Library databases,and all the available studies up to 7 May 2020 were reviewed.The pooled standardized mean difference(SMD)values were calculated to investigate the serum resistin levels in patients with NAFLD and healthy controls.Results:A total of 28 studies were included to investigate the serum resistin levels in patients with NAFLD.Patients with NAFLD had higher serum resistin levels than controls(SMD=0.522,95%confidence interval[CI]:0.004–1.040,I2=95.9%).Patients with nonalcoholic steatohepatitis(NASH)had lower serum resistin levels than the healthy controls(SMD=−0.44,95%CI:−0.83–0.55,I2=74.5%).In addition,no significant difference of serum resistin levels was observed between patients with NAFL and healthy controls(SMD=−0.34,95%CI:−0.91–0.23,I2=79.6%)and between patients with NAFL and NASH(SMD=0.15,95%CI:−0.06–0.36,I2=0.00%).Furthermore,subgroup and sensitivity analyses suggested that heterogeneity did not affect the results of meta-analysis.Conclusions:This meta-analysis investigated the serum resistin levels in adult patients with NAFLD comprehensively.Patients with NAFLD had higher serum resistin levels and patients with NASH had lower serum resistin levels than healthy controls.Serum resistin could serve as a potential biomarker to predict the development risk of NAFLD.