TM6SF2 Variants Research Articles

Clinical Utility of Genetic Variants in PNPLA3 and TM6SF2 to Predict Liver-Related Events in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Fibrosis-4 (FIB-4) index and genetic polymorphisms have been used in assessing the risk of liver-related events (LRE) in metabolic dysfunction-associated steatotic liver disease (MASLD). To establish a more efficient prediction strategy for LRE, we investigated a combined approach that uses the FIB-4 index and genetic polymorphisms. We enrolled 1304 Japanese patients with biopsy-proven MASLD in this longitudinal multicenter cohort study. PNPLA3, TM6SF2, GCKR and MBOAT7 genotypes were genotyped, and polygenic risk score high fat content (PRS-HFC) were calculated. During the follow-up period of 8.1 year, 96 LRE occurred and 53 patients died. PNPLA3, TM6SF2 and GCKR genotypes were associated with LRE development. We divided patients into three groups based on the FIB-4 index and PNPLA3 and TM6SF2 genotype. The cumulative LRE development rate in each group was 2.1%/28.9%/53.5%, respectively, at 10 years. Multivariate analysis revealed hazard ratios (HRs) for LRE of 10.72 in the high-risk group and 4.80 in the intermediate-risk group. Overall survival in each group was 98.8%/85.2%/72.4%, respectively, at 10 years. HRs for prognosis were 8.74 in the high-risk group and 5.62 in the intermediate-risk group. Patients with FIB-4 index > 2.67 and high PRS-HFC had HR of 6.70 for LRE development and HR of 6.07 for prognosis compared to patients with FIB-4 ≤ 2.67. The approach of measuring the FIB-4 index first followed by assessment of genetic polymorphisms efficiently detected patients at high risk of developing LRE. Therefore, this two-step strategy could be used as a screening method in large populations of patients with MASLD.

Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach

Background & AimAn unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. TM6SF2 represents a good candidate for this approach due to its known association with steatotic liver disease (SLD). MethodsWe screened participants with whole-exome sequences in the Penn Medicine Biobank (N>40,000) and the UK Biobank (UKB, N>200,000) for protein-altering variants in TM6SF2 and evaluated their association with liver phenotypes and clinical outcomes. ResultsThree missense variants in TM6SF2 (E167K, L156P, P216L) were associated with an increased risk of clinically-diagnosed and imaging-proven steatosis, independent of PNPLA3 I48M risk allele and hepatitis B/C (p<0.001). E167K homozygotes had significantly increased risk of SLD (OR:5.38, p<0.001), steatohepatitis (OR:5.76, p<0.05) and hepatocellular carcinoma (OR:11.22, p<0.0001) whilst nominal risk of steatohepatitis were present in L156P (OR:2.3, p<0.001) and P216L (OR:4.5, p<0.05) heterozygotes. In addition, carriers of E167K are at a 3-folded increase of at-risk MASH (OR:2.75, p<0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (p<0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (N=105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was strengthened with a gene-burden of rare loss-of-function variants in TM6SF2 demonstrating an increased risk of SLD (OR:4.9, p<0.05), primarily driven by a novel rare stop-gain variant (W35X) in the same directionality. ConclusionThe functional genetic study of protein-altering variants provides insights on the association between loss of TM6SF2 function and steatotic liver disease and poses the bases for future mechanistic studies. Impact and implicationsThe genome-first approach expands insights into genetic risk factors for steatotic liver disease with TM6SF2 being a focal point due to its known association with plasma lipid traits. Our findings validated two missense variants (E167K and L156P) to be associated with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common PNPLA3 I48M risk variant. Notably, we also identified a predicted deleterious missense variant P216L to drive steatotic risk and demonstrated that an aggregated gene burden of rare variants demonstrating complete loss-of-function to be linked to the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of TM6SF2 variants in metabolic dysfunction-associated steatotic liver disease to determine future therapeutic targets.

Relevance of PNPLA3, TM6SF2, HSD17B13, and GCKR Variants to MASLD Severity in an Egyptian Population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a frequent clinical condition globally. Single nucleotide polymorphisms (SNPs) associated with NAFLD have been proposed in the literature and based on bioinformatic screening. The association between NAFLD and genetic variants in Egyptians is still unclear. Hence, we sought to investigate the association of some genetic variants with NAFLD in Egyptians. Egyptians have been categorized into either the MASLD group (n = 205) or the healthy control group (n = 187). The severity of hepatic steatosis and liver fibrosis was assessed by a Fibroscan device. TaqMan-based genotyping assays were employed to explore the association of selected SNPs with MASLD. PNPLA3 rs738409 C>G variant is associated with the presence of MASLD with liver fibrosis, the severity of both hepatic steatosis and liver fibrosis, increased systolic and diastolic blood pressure and increased alanine aminotransferase (all p < 0.05), while the TM6SF2 rs58542926 C>T, HSD17B13 rs9992651 G>A, and GCKR rs1260326 T>C variants were not (all p > 0.05). The TM6SF2 rs58542926 T allele is associated with increased fasting blood glucose and a decreased waist circumference. The GCKR rs1260326 C allele is associated with decreased aspartate transaminase and diastolic blood pressure (all p < 0.05). Only after adjusting for the risk factors (age, sex, BMI, WC, HDL, TG, diabetes mellitus, and hypertension) F2 liver fibrosis score is negatively correlated with the HSD17B13 rs9992651 GA genotype. This study offers evidence for the association of the PNPLA3 rs738409 C>G variant with MASLD among Egyptians and for the association of the PNPLA3 rs738409 G allele, the TM6SF2 rs58542926 T allele, and the GCKR rs1260326 C allele with some parameters of cardiometabolic criteria.

Association of PNPLA3, TM6SF2 and HSD17B13 variants with NAFLD risk in HIV and non-HIV individuals

Association of PNPLA3, TM6SF2 and HSD17B13 variants with NAFLD risk in HIV and non-HIV individuals

Complex effects of sequence variants on lipid levels and coronary artery disease

Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

Metabolic disorders induced by PNPLA3 and TM6SF2 gene variants affect chronic kidney disease in patients infected with non-genotype 3 hepatitis C virus

BackgroundPatients with chronic hepatitis C virus (HCV) infections differ in their risk for metabolic disorders and chronic kidney disease (CKD). The aim of this study was to investigate the effect of metabolic disorders induced by genetic factors on CKD in HCV-infected patients.MethodsPatients with chronic non-genotype 3 HCV infection with or without CKD were examined. PNPLA3 and TM6SF2 variants were determined using high-throughput sequencing. The relationships of variants and different combinations with metabolic disorders were analyzed in CKD patients. Univariate and multivariate analyses were used to identify factors associated with CKD.ResultsThere were 1022 patients with chronic HCV infection, 226 with CKD and 796 without CKD. The CKD group had more severe metabolic disorders, and also had higher prevalences of liver steatosis, the PNPLA3 rs738409 non-CC genotype, and the TM6SF2 rs58542926 CC genotype (all P < 0.05). Relative to patients with the PNPLA3 rs738409 CC genotype, patients with the non-CC genotype had a significantly decreased eGFR and a greater prevalence of advanced CKD (CKD G4-5). Patients with the TM6SF2 rs58542926 CC genotype had a lower eGFR and a higher prevalence of CKD G4-5 than those with the non-CC genotype. Multivariable analysis indicated that multiple metabolic abnormalities, including liver steatosis and the PNPLA3 rs738409 C > G variant, increased the risk of CKD, but the TM6SF2 rs58542926 C > T variant decreased the risk of CKD.ConclusionSpecific PNPLA3 rs738409 and TM6SF2 rs58542926 variants are independent risk factors for CKD in patients with chronic HCV infections and are associated with the severity of renal injury.

An adult-based genetic risk score for liver fat associates with liver and plasma lipid traits in children and adolescents.

Genome-wide association studies have identified steatogenic variants that also showed pleiotropic effects on cardiometabolic traits in adults. We investigated the effect of eight previously reported genome-wide significant steatogenic variants, individually and combined in a weighted genetic risk score (GRS), on liver and cardiometabolic traits, and the predictive ability of the GRS for hepatic steatosis in children and adolescents. Children and adolescents with overweight (including obesity) from an obesity clinic group (n = 1768) and a population-based group (n = 1890) were included. Cardiometabolic risk outcomes and genotypes were obtained. Liver fat was quantified using 1 H-MRS in a subset of 727 participants. Variants in PNPLA3, TM6SF2, GPAM and TRIB1 were associated with higher liver fat (p < .05) and with distinct patterns of plasma lipids. The GRS was associated with higher liver fat content, plasma concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST) and favourable plasma lipid levels. The GRS was associated with higher prevalence of hepatic steatosis (defined as liver fat ≥5.0%) (odds ratio per 1-SD unit: 2.17, p = 9.7E-10). A prediction model for hepatic steatosis including GRS alone yielded an area under the curve (AUC) of 0.78 (95% CI 0.76-0.81). Combining the GRS with clinical measures (waist-to-height ratio [WHtR] SDS, ALT, and HOMA-IR) increased the AUC up to 0.86 (95% CI 0.84-0.88). The genetic predisposition for liver fat accumulation conferred risk of hepatic steatosis in children and adolescents. The liver fat GRS has potential clinical utility for risk stratification.

Behavioural activity pattern, genetic factors, and the risk of nonalcoholic fatty liver disease: A prospective study in the UK Biobank.

Physical activity, sedentary behaviour, and genetic variants have been associated with the nonalcoholic fatty liver disease (NAFLD). However, whether and how the degree of healthy activity patterns may modify the impact of genetic susceptibility on NAFLD remains unknown. Behaviour activity factors were determined according to total physical activity (TPA) and sedentary time. The polygenic risk score (PRS) was calculated by variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Cox regression was used to analyse the associations of genetic and behaviour activity factors with incident NAFLD in the UK Biobank (N = 338 087). During a median follow-up of 12.4 years, 3201 incident NAFLD cases were ascertained. Analyses of TPA and sedentary time simultaneously showed a dose-response association with the risk of NAFLD (ptrend < .001). The association of behaviour activity patterns with NAFLD varied by genetic variants. Of the subjects with high genetic risk, we observed a null protective effect of moderate or high TPA on NAFLD risk, while sitting less than three hours a day significantly decreased the risk of NAFLD (p = 3.50 × 10-4 ). The high genetic risk of NAFLD can also be offset by the combination of moderate physical activity and shorter sedentary time. Moreover, the high genetic risk group has the greatest reduction of 10-year absolute risk (6.95 per 1000 person-years) if reaching both healthy activities. Moderate-to-high physical activity and favourable sedentary behaviour may be lifestyle modifications in preventing NAFLD, which could offset the harmful effect of predisposing genetic factors.

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Nutritional Genomics in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.

Overview of Genetics in Non Alcoholic Fatty Liver Disease: A Futuristic Cognizance

Non Alcoholic Fatty Liver Disease (NAFLD) is an emerging epidemic worldwide. It comprehends simple steatosis to escalating steatosis with associated fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality. It seems to have a robust interconnection with visceral adiposity, Insulin Resistance (IR), inflammation, and environmental factors. Although the pathogenesis of NAFLD is presumed to be linked to lifestyle patterns, nutritional factors, and genetics, the predictor of advancement of this disease spectrum caused by genetics stands imprecise. In the past decade, multiple genome-wide associations and large candidate gene studies have recognised the contribution of several genetic polymorphisms in regulating hepatic lipid metabolism, thus influencing NAFLD establishment and progression. Recent understanding of the genetic underpinning of NAFLD explains the involvement of several common naturally occurring variants in PNPLA3, TM6SF2, MBOAT7, GCKR, LYPLAL1 and PPP1R3B genes in the evolution of the disease. The genetic landscape may play a role to appraise the risk stratification and ascertaining the potential therapeutic target in NAFLD patients. The perspective of this review was to emphasise the genetic basis of the NAFLD spectrum, which modulates the severity and progression of the disease.

Genetic variants associated with steatohepatitis and liver fibrosis in HIV-infected patients with NAFLD.

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver damage in people living with HIV (PLWHIV). Several studies have investigated candidate genes for susceptibility to NAFLD and to steatohepatitis. PNPLA3, TM6SF2, and MBOAT7-TMC4 have been reported to be associated with elevated ALT levels and the histologic parameters of nonalcoholic steatohepatitis and severity of fibrosis. Our objective was to analyze the relationship between PNPLA3, TM6SF2, and MBOAT7-TMC4 and steatosis, steatohepatitis, and liver fibrosis in PLWHIV with NAFLD. Method: A cohort of PLWHIV with persistently elevated aminotransferase levels and suspected NAFLD who underwent liver biopsy and determination of genetic variants was assessed at two large centers in Spain. All participants included in the current study were genotyped for rs738409 (PNPLA3), rs58542926 (TM6SF2), and rs641738 (MBOAT7-TMC4). Results: The study population comprised PLWHIV who were on stable antiretroviral therapy [7.7% women; median age, 49.3 years (44–53.4)]. The median CD4 count was 829 (650–980), 60% had metabolic syndrome, and 18.5% were diabetic. The median BMI was 28.9 (25.5–30.8). Patients with liver steatosis (any grade) vs. nonsteatosis tended to harbor the PNPLA3 G allele variant [57.6% vs. 16.7% (p = 0.09)], but not TM6SF2 or MBOAT7-TMC4 variants. However, those with steatohepatitis vs. nonsteatohepatitis significantly more frequently had the PNPLA3 G allele variant [69.4% vs. 39.1% (p < 0.05)] and the MBOAT7-TMC4 A allele variant [75% vs. 42% (p < 0.05)]. In our cohort, the TM6SF2 gene variant was not associated with steatosis or steatohepatitis. The PNPLA3 G allele variant was associated with steatohepatitis [OR 4.9 (1.3–18); p 0.02] and liver fibrosis [OR 4.3 (1.1–17.4); p 0.04], and the MBOAT7-TMC4 A allele variant was associated with steatohepatitis [OR 6.6 (1.6–27.6); p 0.01]. Conclusion: The PNPLA3 G allele variant and MBOAT7-TMC4 A allele variant were associated with steatohepatitis and liver fibrosis in PLWHIV with persistently elevated aminotransferases and NAFLD. We recommend routine genotyping for PNPLA3 and MBOAT7-TMC4 in PLWHIV with NAFLD to identify those at higher risk of progression.

PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study

BackgroundThe present study investigates if common missense functional variants p.I148M and p.E167K in PNPLA3 and TM6SF2 genes, respectively, associate with development of hepatic fibrosis and cirrhosis in a geographically novel cohort of Pakistani chronic hepatitis C (CHC) patients.MethodsIn total, 502 Pakistani CHC patients [242 males, median age 40 years, 220 with significant hepatic fibrosis, including 114 with cirrhosis] were genotyped for PNPLA3 and TM6SF2 variants using TaqMan genotyping assays. Associations between genotypes, biochemical and clinical parameters were evaluated.ResultsGenotypic distributions for PNPLA3 and TM6SF2 polymorphisms conformed to Hardy–Weinberg equilibrium and did not associate with fibrosis grades ≥ F2 or cirrhosis in any of the genetic models tested (all p = > 0.05). PNPLA3 and TM6SF2 variants did not modulate baseline characteristics and serum markers of liver injury in CHC patients. Similarly, increasing number of risk alleles of PNPLA3 and TM6SF2 polymorphisms had no trend effect on serum liver enzyme activities or proportion of CHC patients with significant or advanced fibrosis or cirrhosis (p = > 0.05). The same trend of no association with hepatic fibrosis or cirrhosis persisted in the multivariate logistic regression models adjusting for age, gender, body mass index and HCV viral load (p = > 0.05).ConclusionsPNPLA3 and TM6SF2 variants do not appear to modulate development of hepatic fibrosis or cirrhosis in present CHC patients of Pakistani origin, and may be of more relevance in liver pathology involving abnormalities in hepatic fat accumulation. These results also reflect the divergent associations observed for different genetic modifiers of hepatic fibrosis and cirrhosis in distinct ethnicities.

Role of NAFLD-associated genetic variants on renal function in patients with nonalcoholic fatty liver disease

Background and Aims : NAFLD is associated with an increased risk of chronic kidney disease (CKD). Also, recent observations focused the attention on the role of PNPLA3 rs738409 variant in the relationship between NAFLD and CKD in non-metabolic patients, but the genetic impact on this association is still matter of debate. We aim to investigate the potential influence of PNPLA3, TM6SF2, MBOAT7 and GCKR gene variants on renal function in a large population of NAFLD patients.

Germline Mutations in CIDEB and Protection against Liver Disease

BackgroundExome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.MethodsWe performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.ResultsThe multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, −1.24 U per liter; 95% confidence interval [CI], −1.66 to −0.83; P=4.8×10−9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10−7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, −0.98; 95% CI, −1.54 to −0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets.ConclusionsRare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.)

FRI506 - Prognostic impact of variants in TM6SF2 and MBOAT7 in patients who have progressed to advanced chronic liver disease

FRI506 - Prognostic impact of variants in TM6SF2 and MBOAT7 in patients who have progressed to advanced chronic liver disease

African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population

Introduction and objectivesPNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. MethodsWe included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. ResultsA total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. ConclusionAmong NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.

Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease.

Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6-12% vs. 2-3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.

HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment.

Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) after hepatitis C treatment. Whether this holds true taking into account carriage of the HSD17B13:TA splice variant, also affecting lipogenesis, and achievement of viral clearance (SVR), is unknown. PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 variants were determined in a cohort of 328 cirrhotic patients free of HCC before starting treatment with direct acting antivirals (DAA). SVR in the study cohort was 96%. At the end of follow-up, N = 21 patients had been diagnosed an HCC; none of the genes included in the GRS was individually associated with HCC development. However, in a Cox proportional hazards model, a GRS > 0.457 predicted HCC independently of sex, diabetes, albumin, INR and FIB4. The fit of the model improved adding treatment outcome and carriage of the HSD17B13:TA splice variant, with sex, GRS > 0.457, HSD17B13:TA splice variant and failure to achieve an SVR (hazard ratio = 6.75, 4.24, 0.24 and 7.7, respectively) being independent predictors of HCC. Our findings confirm that genes modulating liver fat and lipogenesis are important risk factors for HCC development among cirrhotics C treated with DAA.

Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk.

Hepatocellular carcinoma is the most frequent primary liver malignancy and fourth most common cause of cancer-related mortality worldwide. 1 Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017; 3: 524-548 Crossref PubMed Scopus (2549) Google Scholar Although chronic viral hepatitis, particularly due to hepatitis B virus (HBV) infection, is the most common underlying liver disease leading to hepatocellular carcinoma in southeast Asia, alcohol-related liver disease and non-alcoholic fatty liver disease are the predominant causes in Europe and North America. Alcohol-related liver disease and non-alcoholic fatty liver disease are expected to become the leading causes of hepatocellular carcinoma in the future, with HBV and hepatitis C virus infections declining as a result of effective vaccination strategies and treatments. With few exceptions, most hepatocellular carcinoma cases in high-income countries develop in patients with established cirrhosis; alcohol-related cirrhosis is the second most common risk factor for hepatocellular carcinoma in high-income countries, 2 West J Card TR Aithal GP Fleming KM Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study. Aliment Pharmacol Ther. 2017; 45: 983-990 Crossref PubMed Scopus (40) Google Scholar with an annual risk of hepatocellular carcinoma of up to 2·5%. 3 Mancebo A González-Diéguez ML Cadahía V et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol. 2013; 11: 95-101 Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar Alcohol-related hepatocellular carcinoma is a complex disease, but easily discernible clinical risk factors include type 2 diabetes, obesity, and older age. 4 Llovet JM Kelley RK Villanueva A et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7: 6 Crossref PubMed Scopus (708) Google Scholar Sequence variations in specific genes that modify the risk of alcohol-related hepatocellular carcinoma have been identified, mostly by means of candidate gene case-control studies, which either enhance or alleviate the risk of developing hepatocellular carcinoma. However, the genetic risk loci recognised until now only represent a fraction of the heritability risk, suggesting that additional genetic modulators might exist. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar The involvement of the rs738409 locus (in the gene coding for PNPLA3) is widely supported by numerous case-control studies, which show the largest effect size among all previously identified genetic risk variants. Additional loci in genes coding for TM6SF2 (rs58542926) and HSD17B13 (rs72613567:TA) were found to increase and alleviate the risk of hepatocellular carcinoma, respectively. 5 Stickel F Buch S Nischalke HD et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018; 113: 1475-1483 Crossref PubMed Scopus (56) Google Scholar , 6 Stickel F Lutz P Buch S et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology. 2020; 72: 88-102 Crossref PubMed Scopus (52) Google Scholar However, unlike in viral hepatitis-associated hepatocellular carcinoma, 7 Jiang DK Sun J Cao G et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013; 45: 72-75 Crossref PubMed Scopus (242) Google Scholar , 8 Kumar V Kato N Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011; 43: 455-458 Crossref PubMed Scopus (303) Google Scholar a comprehensive and hypothesis-free genome-wide study to detect risk loci that might have remained unidentified for alcohol-related hepatocellular carcinoma so far has been lacking. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association studyWNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. Full-Text PDF