Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal

Bataller, Ramón; North, Kari E.; Brenner, David A.

doi:10.1053/jhep.2003.50127

Cited by 325 publications

(240 citation statements)

References 115 publications

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“…119 Given the observation that a number of individuals with chronic HCV infection have excess hepatic iron, 120 some investigators have examined whether possession of these variants is associated with advanced liver disease. The results of these studies have been discrepant, 119,121 with four studies suggesting an association between possession of HFE variants and increased fibrosis or cirrhosis, 80,92,101,109 and the other studies suggesting that there are no associations. Methodological differences may account for these differing observations.…”

Section: Susceptibility To Persistent Hcv Infectionmentioning

confidence: 97%

Host genetic determinants in hepatitis C virus infection

2004

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In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1*0301 and DRB1*11 with selflimiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1*0301 and DRB1*11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1*11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1*11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.

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Section: Susceptibility To Persistent Hcv Infectionmentioning

confidence: 97%

Host genetic determinants in hepatitis C virus infection

2004

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“…Studies using models of hepatic fibrosis in transgenic mice have revealed IL-1β and TGF-β1 as key players mediating liver fibrogenesis [69,70]. Huang and colleagues [71] investigated the role of P2X 7 R in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl 4 ), reporting that P2X 7 R inhibition with a competitive antagonist (A438079) prevented collagen deposition and also significantly reduced the expression of alpha-smooth muscle actin (α-SMA) and TGF-β1.…”

Section: Hepatic Fibrosismentioning

confidence: 99%

The role of P2X7 receptors in tissue fibrosis: a brief review

Gentile

Natale

Lazzerini

et al. 2015

Purinergic Signalling

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Many previous studies have demonstrated that P2X 7 receptors (P2X 7 Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X 7 R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X 7 R and summarize the current knowledge about the putative role of the P2X 7 R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.

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“…6 Because demographic and environmental factors account for only 17%ϳ30% of fibrosis variability, 7 there is increasing interest in understanding the influence of host genetic factors on liver cirrhosis. 8 Previous studies regarding host genetic factors that are involved in liver fibrosis have been focused on inflammatory and immunoregulatory pathways. Tumor necrosis factor ␣, 9 transforming growth factor ␤1, 10 monocyte chemotactic protein-1, 11 and complement factor V 12 are well-known examples of factors associated with liver fibrosis.…”

mentioning

confidence: 99%

A Novel Nonsynonymous Variant of Matrix Metalloproteinase-7 Confers Risk of Liver Cirrhosis†

Hung

Chang

et al. 2009

Hepatology

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Liver cirrhosis is characterized by progressive accumulation of extracellular matrix following chronic liver injuries. In the extracellular space, the constant turnover of liver matrix is regulated by the matrix metalloproteinase (MMP) class of enzyme. To assess whether genetic variations in MMP would result in diversity of liver cirrhosis, a case-control study of 320 patients with hepatocellular carcinoma, with or without cirrhosis, was conducted. Ten single-nucleotide polymorphism markers from four potential fibrosis-associated genes were selected for genotyping. Among these genes, a nonsynonymous single-nucleotide polymorphism which generates the variation of Gly-137 and Asp-137 in the MMP-7 gene was found to be strongly associated with the development of liver cirrhosis. In contrast to MMP-7(Gly-137) that predominantly secretes out into the cell culture medium, the cirrhosis-associated MMP-7(Asp-137) variant is preferentially localized on the extracellular membranes where it exerts its proteolytic activity on pericellular substrates. Functional analysis demonstrated an increased ability of the MMP-7(Asp-137) variant to associate with the cell surface CD151 molecule. In wound-healing and Boyden chamber assays, cell motility was specifically enhanced with the expression of MMP-7(Asp-137) as compared to the cells expressing MMP-7(Gly-137). These results demonstrate that the MMP-7(Asp-137) variant confers a gain-of-function phenotype for MMP-7. Conclusion: We have identified a novel genetic association of MMP-7(Asp-137) variant with liver cirrhosis in patients with hepatocellular carcinoma. Whether the MMP-7 variant can be a new marker for liver cirrhosis will be further studied.

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Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal

Cited by 325 publications

References 115 publications

Host genetic determinants in hepatitis C virus infection

Host genetic determinants in hepatitis C virus infection

The role of P2X7 receptors in tissue fibrosis: a brief review

A Novel Nonsynonymous Variant of Matrix Metalloproteinase-7 Confers Risk of Liver Cirrhosis†

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