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Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD. [ABSTRACT FROM AUTHOR]

ABSTRACT The prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver‐related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population‐based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies. [ABSTRACT FROM AUTHOR]

17b-Hydroxysteroid dehydrogenase-13 (HSD17B13), a newly identified lipid droplet-associated protein, plays an important role in the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Emerging evidence demonstrates that NASH is an independent risk factor for chronic kidney disease, which is frequently accompanied by renal lipid accumulation. In addition, the HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven NAFLD. At present, the role of HSD17B13 in lipid accumulation in the kidney is unclear. This study utilized bioinformatic and immunostaining approaches to examine the expression and localization of HSD17B13 along the mouse urinary tract. We found that HSD17B13 is constitutively expressed in the kidney, ureter, and urinary bladder. Our findings reveal for the first time, to our knowledge, the precise localization of HSD17B13 in the mouse urinary system, providing a basis for further studying the pathogenesis of HSD17B13 in various renal and urological diseases. NEW & NOTEWORTHY HSD17B13, a lipid droplet-associated protein, is crucial in nonalcoholic fatty liver disease (NAFLD) development. NAFLD also independently raises chronic kidney disease (CKD) risk, often with renal lipid buildup. However, HSD17B13's role in CKD-related lipid accumulation is unclear. This study makes the first effort to examine HSD17B13 expression and localization along the urinary system, providing a basis for exploring its physiological and pathophysiological roles in the kidney and urinary tract. [ABSTRACT FROM AUTHOR]

Background & Aims: Progression to hepatocellular carcinoma (HCC) is restricted by viral suppression in chronic hepatitis B (CHB); however, some patients still progress despite antiviral therapy. Presence of single nucleotide polymorphisms (SNPs) such as PNPLA3 rs738409 and TM6SF2 rs58542926 are associated with the development and progression of steatotic liver disease to HCC, whereas a splice variant in HSD17B13 rs72613567:TA has been shown to be protective. We investigated the role of these SNPs in the development or prognosis of HCC in pure CHB etiology, in the absence of hepatic steatosis, remains unknown. Materials: We analysed PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 SNPs in a prospectively recruited cohort (n=323) consisting of healthy controls, CHB and CHB-HCC patients without hepatic steatosis. SNPs were determined by PCR analysis and associations for the alleles and genotypes were investigated using adjusted-logistic regression analyses. The overall survival (OS) data were collected from CHB-HCC patients for survival analysis. Results: The genotype and allelic distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 were similar between healthy controls, CHB, and CHB-HCC groups. No genotype, allele or haplotype analysis was found to be associated with increased risk for CHB-HCC. Survival analysis revealed no genotype or allele to be associated with OS in patients with CHB-HCC. Conclusions: We could not demonstrate any association of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 with the development or prognosis of CHB-HCC, supporting the initial hypothesis that they should be considered specific hotspots for liver diseases characterized with hepatic steatosis. [ABSTRACT FROM AUTHOR]

Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (CDAHFD)-induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.

Summary: Background: Several genetic variants are associated with chronic liver disease. The role of these variants in outcomes after liver transplantation (LT) is uncertain. The aim of this study was to determine if donor genotype at risk-associated variants in PNPLA3 (rs738409 C>G, p.I148M) and HSD17B13 (rs72613567 T>TA; rs80182459, p.A192Lfs∗8) influences post-LT survival. Methods: In this retrospective cohort study, data on 2346 adults who underwent first-time LT between January 1, 1999 and June 30, 2020 and who had donor DNA samples available at five large Transplant Immunology Laboratories in Texas, USA, were obtained from the United Network for Organ Sharing (UNOS). Duplicates, patients with insufficient donor DNA for genotyping, those who were

The identification of genetic variants associated with fatty liver disease (FLD) from genome-wide association studies started in 2008 when single nucleotide polymorphisms in PNPLA3 , the gene encoding patatin-like phospholipase domain-containing 3, were found to be associated with altered hepatic fat content. Since then, several genetic variants associated with protection from, or an increased risk of, FLD have been identified. The identification of these variants has provided insight into the metabolic pathways that cause FLD and enabled the identification of potential therapeutic targets. In this mini-review, we will examine the therapeutic opportunities derived from genetically validated targets in FLD, including oligonucleotide-based therapies targeting PNPLA3 and HSD17 B 1 3 that are currently being evaluated in clinical trials for the treatment of NASH (non-alcoholic steatohepatitis). [ABSTRACT FROM AUTHOR]

Metabolism-related fatty liver disease (MAFLD) is the most common form of chronic liver disease in the world. Its pathogenesis is influenced by both environmental and genetic factors. With the upgrading of gene screening methods and the development of human genome project, whole genome scanning has been widely used to screen genes related to MAFLD, and more and more genetic variation factors related to MAFLD susceptibility have been discovered. There are genetic variants that are highly correlated with the occurrence and development of MAFLD, and there are genetic variants that are protective of MAFLD. These genetic variants affect the development of MAFLD by influencing lipid metabolism and insulin resistance. Therefore, indepth analysis of different mechanisms of genetic variation and targeting of specific genetic variation genes may provide a new idea for the early prediction and diagnosis of diseases and individualized precision therapy, which may be a promising strategy for the treatment of MAFLD. [ABSTRACT FROM AUTHOR]

Genetic variants in 17-β hydroxysteroid dehydrogenase 13 (HSD17B13) were demonstrated to protect against NAFLD, which is highly related with insulin resistance and dyslipidemia. However, the effects of NAFLD associated HSD17B13 variants on circulating glucose and lipids have not been adequately investigated in children. This study aimed to investigate associations between single nucleotide polymorphisms (SNPs) of HSD17B13 and NAFLD or its related phenotypes, such as blood glucose and serum lipids in Chinese children. We studied 1027 Chinese Han children aged 7–18 years old, which included 162 NAFLD children and 865 controls without NAFLD. Three SNPs (rs13112695, rs7692397, rs6834314) in HSD17B13 were genotyped. The multivariable logistic and linear regression models were applied to detect the associations between three SNPs and NAFLD or its related phenotypes [alanine transaminase (ALT), fasting plasma glucose (FPG) and serum lipids]. The effect allele A of rs7692397 was negatively associated with FPG [β (SE) = −0.088 (0.027) mmol/L, P = 0.001], whereas the effect allele G of rs6834314 was positively associated with FPG (β (SE) = 0.060 (0.019) mmol/L, P = 0.002). After Bonferroni correction, the significant associations still remained (both P < 0.0024). No significant associations were found for NAFLD or serum lipids. The study firstly revealed the association between two HSD17B13 variants and FPG in Chinese children, providing evidence for HSD17B13 variants and abnormal glucose metabolism. • HSD17B13 rs6834314 was not protected against NAFLD in Chinese children. • A-allele of HSD17B13 rs7692397 was negatively associated with fasting plasma glucose. • G-allele of HSD17B13 rs6834314 was positively associated with fasting plasma glucose. [ABSTRACT FROM AUTHOR]

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk. [ABSTRACT FROM AUTHOR]

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Autoimmune hepatitis (AIH) is a rare entity; in addition, single-nucleotide polymorphisms (SNPs) may impact its course and outcome. We investigated liver-related SNPs regarding its activity, as well as in relation to its stage and treatment response in a Central European AIH cohort. Methods: A total of 113 AIH patients (i.e., 30 male/83 female, median 57.9 years) were identified. In 81, genotyping of PNPLA3-rs738409, MBOAT7-rs626238, TM6SF2-rs58542926, and HSD17B13-rs72613567:TA, as well as both biochemical and clinical data at baseline and follow-up, were available. Results: The median time of follow-up was 2.8 years; five patients died and one underwent liver transplantation. The PNPLA3-G/G homozygosity was linked to a worse treatment response when compared to wildtype [wt] (ALT 1.7 vs. 0.6 × ULN, p < 0.001). The MBOAT7-C/C homozygosity was linked to non-response vs. wt and heterozygosity (p = 0.022). Male gender was associated with non-response (OR 14.5, p = 0.012) and a higher prevalence of PNPLA3 (G/G vs. C/G vs. wt 41.9/40.0/15.0% males, p = 0.03). The MBOAT7 wt was linked to less histological fibrosis (p = 0.008), while no effects for other SNPs were noted. A polygenic risk score was utilized comprising all the SNPs and correlated with the treatment response (p = 0.04). Conclusions: Our data suggest that genetic risk variants impact the treatment response of AIH in a gene-dosage-dependent manner. Furthermore, MBOAT7 and PNPLA3 mediated most of the observed effects, the latter explaining, in part, the predisposition of male subjects to worse treatment responses. [ABSTRACT FROM AUTHOR]

Background: To establish a treatment option for liver fibrosis, the possibility of the drug repurposing theory was investigated, with a focus on the off-target effects of active pharmaceutical ingredients. Methods: First, several active pharmaceutical ingredients were screened for their effects on the gene expression in the hepatocytes using chimeric mice with humanized hepatocytes. As per the gene expression-based screening assay for 36 medications, we assessed the mechanism of the antifibrotic effect of letrozole, a third-generation aromatase inhibitor, in mouse models of liver fibrosis induced by carbon tetrachloride (CCl4) and a methionine choline-deficient (MCD) diet. We assessed liver histology, serum biochemical markers, and fibrosis-related gene and protein expressions in the hepatocytes. Results: A gene expression-based screening assay revealed that letrozole had a modifying effect on fibrosis-related gene expression in the hepatocytes, including YAP, CTGF, TGF-β, and CYP26A1. Letrozole was administered to mouse models of CCl4- and MCD-induced liver fibrosis and it ameliorated the liver fibrosis. The mechanisms involved the inhibition of the Yap-Ctgf profibrotic pathway following a decrease in retinoic acid levels in the hepatocytes caused by suppression of the hepatic retinol dehydrogenase, Hsd17b13 and activation of the retinoic acid hydrogenase, Cyp26a1. Conclusions: Letrozole slowed the progression of liver fibrosis by inhibiting the Yap-Ctgf pathway. The mechanisms involved the modification of the Hsd17b13 and Cyp26a1 expressions led to the suppression of retinoic acid in the hepatocytes, which contributed to the activation of Yap-Ctgf pathway. Because of its off-target effect, letrozole could be repurposed for the treatment of liver fibrosis. The third-generation aromatase inhibitor letrozole ameliorated liver fibrosis by suppressing the Yap-Ctgf pathway by partially modifying the Hsd17b13 and Cyp26a1 expressions, which reduced the retinoic acid level in the hepatocytes. The gene expression analysis using chimeric mice with humanized liver revealed that the mechanisms are letrozole specific and, therefore, may be repurposed for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

The knowledge on the genetic component of non-alcoholic fatty liver disease (NAFLD) has grown exponentially over the last 10 to 15 years. This review summarizes the current evidence and the latest developments in the genetics of NAFLD and non-alcoholic steatohepatitis (NASH) from the immune system’s perspective. Activation of innate and or adaptive immune response is an essential driver of NAFLD disease severity and progression. Lipid and immune pathways are crucial in the pathophysiology of NAFLD and NASH. Here, we highlight novel applications of genomic techniques, including single-cell sequencing and the genetics of gene expression, to elucidate the potential involvement of NAFLD/NASH-risk alleles in modulating immune system cells. Together, our focus is to provide an overview of the potential involvement of the NAFLD/NASH-related risk variants in mediating the immune-driven liver disease severity and diverse systemic pleiotropic effects.

A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinical, demographic, and biochemical data, and we performed a genotyping analysis for common variants previously associated with liver disease risk (HSD17B13 rs72613567:TA and PNPLA3 rs738409). Patients homozygous for the TA allele showed a higher MELD score (p = 0.047), Child–Turcotte–Pugh score (p = 0.014), and INR levels (p = 0.046), as well as decreased albumin (p = 0.004) at baseline. After multivariate analysis, patients with the "protective" variant indeed had an increased risk of hepatic decompensation [aHR 2.37 (1.09–5.06); p = 0.029] and liver-related mortality [aHR 2.32 (1.20–4.46); p = 0.012]. Specifically, these patients had an increased risk of developing ascites (Log-R 11.6; p < 0.001), hepatic encephalopathy (Log-R 10.2; p < 0.01), and higher mortality (Log-R 14.1; p < 0.001) at 5 years of follow-up. Interactions with the etiology of the cirrhosis and with the variant rs738409 in PNPLA3 are also described. These findings suggest that the variant rs72613567:TA in HSD17B13 has no protective effect, but indeed increases the risk of decompensation and death in patients with advanced chronic liver disease. [ABSTRACT FROM AUTHOR]

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk.

Summary: Background: Human body microbiotas are influenced by several factors, including the interaction of the host with the environment and dietary preferences. The role of host genetics in modulating the liver microbiota in the context of NAFLD remains unknown. To address this gap, we examined the interplay between the liver metataxonomic profile and host genetics. Methods: We obtained 16S rRNA gene sequences from liver biopsies and genotypes by Taqman-assays in 116 individuals. We compared taxon abundance at the genus level across host genotypes using dominant models of inheritance. We focused the analysis on variants influencing the risk/ protection against NAFLD-histological severity (PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and HSD17B13-rs72613567) and a variant influencing macronutrient intake (FGF21-rs838133). We also explored the variants' combined effect via a polygenic risk score (PRS). Findings: We identified at least 18 bacterial taxa associated with variants in the selected loci. Members of the Gammaproteobacteria class were significantly enriched in carriers of the rs738409 and rs58542926 risk-alleles, including Enterobacter (fold change [FC]=6.2) and Pseudoalteromonas (FC=2) genera, respectively. Lawsonella (1.6-FC), Prevotella_9 (FC=1.5), and Staphylococcus (FC=1.3) genera were enriched in rs838133-minor allele carriers, which is linked to sugar consumption and carbohydrate intake. Tyzzerella abundance (FC=2.64) exhibited the strongest association (p = 0.0019) with high PRS values (>4 risk alleles). The percentage of genus-level taxa variation explained by the PRS was ∼7.4%, independently of liver steatosis score and obesity. Interpretation: We provided evidence that genetic variation may influence the liver microbial DNA composition. These observations may represent potentially actionable mechanisms of disease.

There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3 , TM6SF2 , MBOAT7 , HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D 5 -glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D 2 O (n = 61). We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates. [Display omitted] • The pathogenesis of NAFLD can be partly explained by a metabolic component and partly by a genetic component. • The mechanisms underlying these components are fundamentally different. • The metabolic component is characterized by a substrate surplus and increased rates of adipose tissue lipolysis and hepatic DNL. • The genetic component is characterized by increased hepatic mitochondrial redox state and inhibition of pathways dependent on TCA cycle activity, such as DNL. • These components additively increase the severity of NAFLD. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine. Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score. Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3 - G -allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887–4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097–2.226], P = 0.013). SERPINA1 - Z -allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182–7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153–1.743], P = 0.020). PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic. [ABSTRACT FROM AUTHOR]

A splice variant in HSD17B13 gene is demonstrated to protect against nonalcoholic fatty liver disease (NAFLD), and mitigate the effect of Patatin-like phospholipase domain-containing 3 (PNPLA3 -I148M). It is being explored as a putative drug target and in polygenic risk scores. Based on whole exome sequencing (WES) in our cohort of biopsy proven NAFLD and limited data on the variant in our ethnicity, we sought to explore its role. This is a cross-sectional study that recruited 1,020 individuals with ultrasound/biopsy-confirmed NAFLD and matched controls. Liver enzymes and lipid profiles were estimated (Beckman coulter LX750/DXH800); WES was performed in NAFLD patients and controls (Illumina; HiSeqX); HSD17B13 -A-INS/I148M- PNPLA3 variants were genotyped (sequencing/qR T-PCR); HSD17B13 protein expression was estimated (immunohistochemistry); the Student's t-test/Mann–Whitney U/Chi-square test and odds ratio (95% confidence interval) were used. There was no significant difference (Odds ratio = 0.76; 95% CI −0.57 to 1.03; P = 0.76) in the frequency of the rs72613567-A-INS between controls and patients (17.8% vs. 14.4%). No difference in the ALT (Alanine transaminase; 72.24 ± 65.13 vs. 73.70 ± 60.06; P = 0.51) and AST levels (Aspartate aminotransferase; 60.72 ± 55.59 vs. 61.63 ± 60.33; P = 0.91) between HSD17B13- wild and variant carriers were noted. Significantly elevated liver enzymes were seen in PNPLA3 -148-variant/ HSD17B13- wild compared with PNPLA3 -148-variant/ HSD17B13- variant (90.44 ± 59.0 vs. 112.32 ± 61.78; P = 0.02). No difference in steatosis (P = 0.51) between HSD17B13 -wild and variant carriers was noted. No other variants in the intron–exon boundaries were identified. Although, protein expression differences were noted between wild and variant carriers, no difference in the extent of steatosis was seen. Our study reports lack of association of the splice variant with reduced risk of NAFLD, and mitigating the effect of PNPLA3 variant. Ethnicity-based validation must be carried out before including it in assessing protection against NAFLD. The relevance of genetic susceptibility in NAFLD has been reaffirmed by genome wide/exome wide association studies. A study demonstrated protective role of splice variant in HSD17B13 gene against NAFLD and mitigate the effect of PNPLA3 -I148M. Whole exome sequencing in our cohort of biopsy proven-NAFLD also identified the splice variant and in view of limited data, we validated it in the Indian ethnicity. HSD17B13 -A-INS /PNPLA3 -I148M variants were genotyped and protein expression estimated. There was no significant difference in rs72613567-A-INS between controls and patients (17.8% vs. 14.4%). No difference was seen in the liver enzymes and steatosis between HSD17B13- wild and variant carriers. Although, protein expression differences were noted between wild and variant carriers, no difference in the extent of steatosis was seen. We report lack of association of splice variant with reduced risk of NAFLD and mitigating effect on PNPLA3 variant. Ethnicity based validation must be done before including it in assessing protection against NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

PNPLA3 rs 738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 have been associated with an increased risk of liver-related events (LREs) in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). In this study, we investigated the combined effects of these variants on LREs. The longitudinal multicenter cohort study enrolled 1178 patients with biopsy-proven MASLD. We calculated the genetic risk of hepatic fibrosis and LRE according to the impact of these variants. Patients with genetic fibrosis scores of 2, 3, and 4 or 5 were at greater risk than patients with scores of 0 or 1, with odds ratios of 2.45 (95% CI, 1.27–4.74), 2.14 (95% CI, 1.17–3.94), and 2.54 (95% CI, 1.35–4.77), respectively. Multivariate analysis revealed that PNPLA3 and TM6SF2 , but not HSD17B13 , were associated significantly with LRE development. The hazard ratio of the genetic high-risk group for LRE was 1.91 (95% CI, 1.20–3.04). The higher risk of LRE development in the genetic high-risk group also was seen in patients with F ≥ 3 or Fibrosis-4 index > 2.67. The hazard ratios of the genetic high-risk group for LRE were greater in patients without obesity, without diabetes, and of younger age compared with patients with obesity, with diabetes, or of older age, respectively. This combination of MASLD-related genetic variants is useful for predicting LREs in Japanese patients with MASLD. The genetic risk according to these variants is useful for LRE risk assessment, especially in patients without metabolic risk factors or in younger patients in Japan. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors. Design: Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study. Results: 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added. Conclusion: In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis (AH) is a severe and life‐threatening alcohol‐associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. Methods: A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O‐acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. Results: We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15–2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04–1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End‐stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921). Conclusion: PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity. [ABSTRACT FROM AUTHOR]

Background & Aims: Recently, the variant rs72613567:TA in the 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been associated with reduced levels of ALT and AST and a reduced risk of alcohol‐related liver disease (ALD) in the European population. Therefore, the aim of this study was to investigate the association between the polymorphisms of HSD17B13 and ALD, liver serum markers and patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) p.I148M in the Chinese Han population. Methods: A case‐control study was performed from five centres and included 769 ALD patients and 767 healthy controls. Two SNPs (rs72613567 and rs6834314) in HSD17B13 were genotyped using the Sequenom MassArray system and allele association analysis was performed using PLINK 1.90 software. Results: HSD17B13 rs72613567:TA allele was associated with a reduced risk of ALD by 19% (95% confidence interval [CI]: 0.05‐0.31, P =.01), uniformly, the G allele in the rs6834314 reduced the risk of ALD by 19% (95% CI: 0.05‐0.31, P = 8.28 × 10−3). And the genotypes of two SNPs were associated with reducing the risk of ALD in three genetic model analysis. In addition, we found that TA allele was associated with lower levels of serum ALT, AST and GGT (P =.005,.007 and.02, respectively), higher level of serum ALB (P =.02), but not associated with ALP. In this cohort, the interaction between HSD17B13 rs72613567 and the steatogenic allele PNPLA3 rs738409 was not validated. Conclusion: The present study revealed that HSD17B13 rs72613567 was significantly associated with a reduced risk of ALD in Chinese Han population. [ABSTRACT FROM AUTHOR]

Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Case-control analysis identified signals showing p values ≤5 × 10−8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16 ; chr4 HSD17B13 ; chr19 TM6SF2 ; chr22 PNPLA3) together with 2 other signals with p <1 × 10−7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10−8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16 , the genome-wide significance signals were replicated. This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. • Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. • Main analysis shows genome-wide significance for PNPLA3, TM6SF2, HSD17B13 and GCKR. • Sub-analyses show significance near LEPR for NASH and near PYGO1 for steatosis. • Except for GCKR , the genome-wide significant signals were replicated. [ABSTRACT FROM AUTHOR]

Background & Aims: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non‐alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD. Methods: We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy‐proven NAFLD diagnosed during 2002‐2019. During follow‐up, 14 patients (4.8%) developed hepatocellular carcinoma. Results: Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P =.041), but not HSD17B13 AG/GG (P =.776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis. Conclusions: In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. Methods: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. Results: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r²=0.96) also showed no overall association with liver disease, but the GG-genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). Conclusions: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology. [ABSTRACT FROM AUTHOR]

17β-Hydroxysteroid dehydrogenases (HSD17Bs) comprise a large family of 15 members that are mainly involved in sex hormone metabolism. Some HSD17Bs enzymes also play key roles in cholesterol and fatty acid metabolism. Recent study showed that hydroxysteroid 17β-dehydrogenase 13 (HSD17B13), an enzyme with unknown biological function, is a novel liver-specific lipid droplet (LD)-associated protein in mouse and humans. HSD17B13 expression is markedly upregulated in patients and mice with non-alcoholic fatty liver disease (NAFLD). Hepatic overexpression of HSD17B13 promotes lipid accumulation in the liver. In this review, we summarize recent progress regarding the role of HSD17B13 in the regulation of hepatic lipid homeostasis and discuss genetic, genomic and proteomic evidence supporting the pathogenic role of HSD17B13 in NAFLD. We also emphasize its potential as a biomarker of advanced liver disease, such as non-alcoholic steatohepatitis (NASH) and liver cancer. • NAFLD is characterized by a massive accumulation of lipid droplets. • HSD17B13 is a newly identified liver restricted LD-associated protein. • HSD17B13 expression is markedly upregulated in the livers of patients and mice with NAFLD. • A variant in HSD17B13 (rs72613567:TA) is negatively associated with ALT and AST levels. • The physiological function of HSD17B13 remains largely uncharacterized. [ABSTRACT FROM AUTHOR]

Here, the authors review the remarkable genetic discoveries that have illuminated the biology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The authors integrate genes associated with NAFLD and NASH into regulatory pathways to elucidate the disease pathogenesis. They review the evidence for molecular mediators of chronic liver damage, which suggests that convergent pathophenotypes, including inflammation and fibrosis, share common genetic modifiers. They further demonstrate that genes involved in the genetic susceptibility of NAFLD and NASH participate in cross-phenotype associations with diseases of the metabolic syndrome, including type 2 diabetes, obesity, and cardiovascular disease. However, immune-related loci associated with NAFLD and NASH exhibit some level of pleiotropy influencing disparate phenotypes, such as premature birth or sepsis. They finally focus on the translation of current genetic knowledge of NAFLD and NASH toward precision medicine. They provide evidence of genetic findings that can be leveraged to identify therapeutic targets. [ABSTRACT FROM AUTHOR]

Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the United States have a high prevalence of PNPLA3 I148M, which increases liver disease risk, and a low prevalence of HSD17B13 predicted loss-of-function (pLoF) variants, which reduce risk. Less is known about the prevalence of liver disease–associated variants among Hispanic/Latino subpopulations defined by country of origin and genetic ancestry. We evaluated the prevalence of HSD17B13 pLoF variants and PNPLA3 I148M, and their associations with quantitative liver phenotypes in Hispanic/Latino participants from an electronic health record–linked biobank in New York City. This study included 8739 adult Hispanic/Latino participants of the Bio Me biobank with genotyping and exome sequencing data. We estimated the prevalence of Hispanic/Latino individuals harboring HSD17B13 and PNPLA3 variants, stratified by genetic ancestry, and performed association analyses between variants and liver enzymes and Fibrosis-4 (FIB-4) scores. Individuals with ancestry from Ecuador and Mexico had the lowest frequency of HSD17B13 pLoF variants (10%/7%) and the highest frequency of PNPLA3 I148M (54%/65%). These ancestry groups had the highest outpatient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and the largest proportion of individuals with a FIB-4 score greater than 2.67. HSD17B13 pLoF variants were associated with reduced ALT level (P =.002), AST level (P <.001), and FIB-4 score (P =.045). PNPLA3 I148M was associated with increased ALT level, AST level, and FIB-4 score (P <.001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (P =.006). Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals. [ABSTRACT FROM AUTHOR]

The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In clinical practices, the therapeutic outcomes and prognosis of hepatocellular carcinoma (HCC) patients with different tumor numbers after surgery are very different; however, the underlying mechanisms of the tumorigenesis and development of HCC with different tumor numbers are still not well understood. Here, we systematically compared the overall proteome profiles between the primary HCC with single and multiple lesions using iTRAQ-based quantitative proteomics approach. We identified that 107 and 330 proteins were dysregulated in HCC tissue with multiple lesions (MC group) and HCC tissue with a single lesion (SC group), compared with their non-cancerous tissue (MN and SN groups) respectively. The dysregulated proteins in MC group are concentrated in UBC signaling pathway and NFκB signaling pathway, but the dysregulated proteins in SC group are more concentrated in ERK signaling pathway and the NFκB signaling pathway. These information revealed that there might be different molecular mechanisms of the tumorigenesis and development of the HCC with single and multiple lesions. Furthermore, HSD17B13 were only down-regulated in MC group while HK2 were only up-regulated in SC group among these dysregulated proteins. Therefore, the protein HSD17B13 and HK2 might be potential biomarkers for the primary HCC with single and multiple lesions. [ABSTRACT FROM AUTHOR]

As diet and lifestyle have changed, fatty liver disease (FLD) has become more and more prevalent. Many genetic risk factors, such as variants of PNPLA3, TM6SF2, GCKR, and MBOAT7, have previously been uncovered via genome wide association studies (GWAS) to be associated with FLD. In 2018, a genetic variant (rs72613567, T > TA) of hydroxysteroid 17-β dehydrogenase family 13 (HSD17B13) was first associated with a lower risk of developing alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) in minor allele carriers. Other HSD17B13 variants were also later linked with either lower inflammation scores among NAFLD patients or protection against NAFLD (rs6834314, A > G and rs9992651, G > A) respectively. HSD17B13 is a lipid droplet-associated protein, but its function is still ambiguous. Compared to the other genetic variants that increase risk for FLD, HSD17B13 variants serve a protective role, making this gene a potential therapeutic target. However, the mechanism by which these variants reduce the risk of developing FLD is still unclear. Because studies in cell lines and mouse models have produced conflicting results, human liver tissue modeling using induced pluripotent stem cells may be the best way to move forward and solve this mystery. [ABSTRACT FROM AUTHOR]

Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. Results: the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). Conclusions: in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD. [ABSTRACT FROM AUTHOR]

Genetic variants including PNPLA3-rs738409 C>G, TM6SF2-rs58542926 C>T, MBOAT7-rs641738 C>T, and HSD17B13-rs72613567 T>TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure. [ABSTRACT FROM AUTHOR]

Introduction: An interaction between metabolic triggers and inherited predisposition underpins the development and progression of non alcoholic fatty liver disease (NAFLD) and fatty liver disease in general. Among the specific NAFLD risk variants, PNPLA3 rs738409 C>G, encoding for the p.I148M protein variant, accounts for the largest fraction of liver disease heritability and is being intensively scrutinized. It promotes intrahepatic lipid accumulation and is associated with lipotoxicity and the more severe phenotypes, including fibrosis and carcinogenesis. Therefore, PNPLA3 appears as an appealing therapeutic target to counter NAFLD progression., Areas Covered: The scope of this review is to briefly describe the PNPLA3 gene and protein function before discussing therapeutic approaches for fatty liver aiming at this target. Literature review was carried out searching through PubMed and clinicaltrials.gov website and focusing on the most recent works and reviews., Expert Opinion: The main therapeutic strategies under development for NAFLD have shown variable efficacy and side-effects likely due to disease heterogeneity and lack of engagement of the main pathogenic drivers of liver disease. To overcome these limitations, new strategies are becoming available for targeting PNPLA3 p.I148M, responsible for a large fraction of disease susceptibility.