Impact of common risk factors of fibrosis progression in chronic hepatitis C

Rüeger, Sina; Bochud, Pierre–Yves; Dufour, Jean–François; Müllhaupt, Beat; Semela, David; Heim, Markus H.; Moradpour, Darius; Cerny, Andreas; Malinverni, Raffaele; Booth, David R.; Suppiah, Vijayaprakash; George, Jacob; Argiro, Laurent; Halfon, Philippe; Bourlière, Marc; Talal, Andrew H.; Jacobson, Ira M.; Patin, Étienne; Nalpas, Bertrand; Poynard, Thierry; Pol, Stanislas; Abel, Laurent; Kutalik, Zoltán; Negro, Francesco

doi:10.1136/gutjnl-2014-306997

Cited by 89 publications

(83 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The stronger effect of PNPLA3 in non-obese patients fits with a recent study showing that the amount of liver fat is similar in obese NAFLD compared to PNPLA3 rs738409 G-associated NAFLD. Our data confirmed the link reported in CHC between the severity of steatosis and the PNPLA3 rs738409 G variant, [8][9][10][11][12][13][14][15] but we were unable to confirm a direct association with the severity of fibrosis. Differences in clinical, metabolic and histological characteristics of studied populations, as well as in the analysis of data could explain this difference.…”

Section: Discussionsupporting

confidence: 68%

“…[5][6][7] Some studies on cohorts of mostly genotype 1 (G1) chronic hepatitis C (CHC) patients have reported an association between the PNPLA3 rs738409 G variant and the severity of both steatosis and fibrosis, the risk of fibrosis progression and HCC occurrence, and the response to pegylated interferon plus ribavirin therapy. [8][9][10][11][12][13][14][15] Bedossa et al, in liver biopsies from CHC patients, recently characterised the presence of histological features of steatohepatitis, showing that the occurrence of NASH in this setting not only was related to a poor atrisk metabolic profile but was also a risk factor for the severity of liver damage. 16 This study however did not investigate the impact of genetic background on the presence of steatohepatitis in the context of CHC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non‐obese subjects with hepatitis C

Petta

Vanni²,

Bugianesi³

et al. 2015

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SummaryBackgroundThe PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non‐alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC).AimTo test in genotype 1(G1)‐CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis.MethodsFour hundred and thirty‐four consecutively biopsied Caucasian G1‐CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients.ResultsThe prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03–2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00–1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04–4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04–1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non‐obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26–3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05–4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002).ConclusionIn patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non‐obese subjects.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non‐obese subjects with hepatitis C

Petta

Vanni²,

Bugianesi³

et al. 2015

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…A recent study by us indicates that this is also the case for liver fibrosis. Thus, a significant portion of the fibrosis progression rate could not be explained by common cofactors including clinical variables and SNPs discovered by GWAS, based on a low pseudo-R 2 of the multivariate logistic regression model of fibrosis progression [114]. This observation indicates that there are additional loci affecting liver injury that remain to be uncovered even after the GWAS era.…”

Section: Genes and Host-virus Interactions: Open Questions And Challementioning

confidence: 94%

Host – hepatitis C viral interactions: The role of genetics

Heim

Bochud

George

2016

Journal of Hepatology

View full text Add to dashboard Cite

Hepatitis C virus (HCV) is a major cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN)-induced genes, and a delayed induction of adaptive immune responses. There is a strong association between genetic variants in the IFNλ (IL28B) locus with the rate of spontaneous clearance. Individuals with the ancestral IFNλ4 allele capable of producing a fully active IFNλ4 are paradoxically not able to clear HCV in the acute phase and develop chronic hepatitis C (CHC) with more than 90% probability. In the chronic phase of HCV infection, the wild-type IFNλ4 genotype is strongly associated with an induction of hundreds of classical type I/type III IFN stimulated genes in hepatocytes. However, the activation of the endogenous IFN system in the liver is ineffective in clearing HCV, and is even associated with impaired therapeutic responses to pegylated (Peg)IFNα containing treatments. While the role of genetic variation in the IFNλ locus to the outcome of CHC treatment has declined, it is clear that variation not only at this locus, but also at other loci, modulate clinically important liver phenotypes, including inflammation, fibrosis progression and the development of hepatocellular cancer. In this review, we summarize current knowledge about the role of genetics in the host response to viral hepatitis and the potential future evolution of knowledge in understanding host-viral interactions.

show abstract

“…The initial association between MERTK rs4374383 and development of fibrosis in chronic HCV disease was observed in a GWAS; in this study, the association was observed only in a sub-group of HCV patients who received blood transfusions [12]. Later, the MERTK SNP significantly added risk to accelerated fibrosis progression rate in the Swiss Hepatitis C Cohort Study [10]. Interestingly, a recent study also showed that the rs4374383 AA genotype was protective against F2-F4 fibrosis in patients with NAFLD [32].…”

Section: Discussionmentioning

confidence: 89%

“…26 No 1: 37-43 that the patatin-like phospholipase domain containing 3 (PNPLA3) gene polymorphism rs738409 was associated with NAFLD [8] and affects the activities of liver enzymes in plasma [9]. The PNPLA3 gene polymorphism rs738409 was also shown to accelerate liver fibrosis progression rate in HCV-infected patients [10] and contribute to the development of alcoholic liver cirrhosis [11]. Further genetic association studies discovered two other loci harboring RNF7, which is also known as SAG (sensitive to apoptosis gene), and proto-oncogene tyrosine-protein kinase MER (MERTK), which may influence the development of fibrosis in chronic hepatitis C [12].…”

Section: Introductionmentioning

confidence: 99%

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

Kupčinskas

Valantienė

Varkalaitė

et al. 2017

JGLD

View full text Add to dashboard Cite

Background & Aims: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population.Methods: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays.Results: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020).Conclusion: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions.Abbreviations: GWAS: Genome-wide association studies; HBV: hepatitis B virus; HCV: hepatitis C virus; HH: hereditary hemochromatosis; MERTK: proto-oncogene tyrosine-protein kinase MER; NAFLD: non-alcoholic fatty liver disease; PCSK7: proprotein convertase 7; PNPLA3: patatin-like phospholipase domain containing 3; RNF7: SAG sensitive to apoptosis gene; SNP: single nucleotide polymorphism.

show abstract

Impact of common risk factors of fibrosis progression in chronic hepatitis C

Abstract: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

Cited by 89 publications

References 43 publications

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non‐obese subjects with hepatitis C

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non‐obese subjects with hepatitis C

Host – hepatitis C viral interactions: The role of genetics

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

Contact Info

Product

Resources

About