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• W2034641100 abstract "HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed. HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed. Chronic hepatitis C is the most common cause of cirrhosis and the first indication for liver transplantation in Europe and the United States. The progression from early stage of fibrosis to cirrhosis varies widely among patients with chronic hepatitis C. Identifying patients in whom fibrosis will progress rapidly as well as non-responders is crucial for disease prognosis. Some defined markers such as male gender, age, alcohol, and obesity may play a role in accelerating fibrosis and treatment failure. The current standard of care for HCV genotype 1 patients is triple therapy with the addition of protease inhibitors (boceprevir and telaprevir) to pegylated interferon (PegIFN) plus ribavirin (RBV). For genotype non-1 patients, treatment is still PegIFN and RBV. The prediction of non-response to treatment is mandatory to avoid side effects and reduce costs. Since the sequencing of the entire human genome in 2001, major advances have been made in genotyping technologies, in particular, the decrease in the cost of genotyping, the large-scale discovery of single nucleotide polymorphisms (SNPs), the development of massive multiplexed genotyping and the efforts of SNPs consortiums and the HapMap project. Since 2009, at least 4 different GWAS have investigated genomic markers associated with a response to PegIFN/RBV in patients with chronic HCV (CHC). The same SNPs located in the promoter region of IL-28B were highly associated with natural and treatment-induced viral clearance [[1]Afdhal N.H. McHutchison J.G. Zeuzem S. Mangia A. Pawlotsky J.M. Murray J.S. et al.Hepatitis C pharmacogenetics: state of the art in 2010.Hepatology. 2011; 1: 336-345Crossref Scopus (73) Google Scholar]. The aim of this review was to present and discuss the major genomic markers that have been associated with either fibrosis progression or treatment response in patients with CHC. The combination of these different markers may help identify a strong predictive genetic signature for fibrosis progression and treatment response. When the GWAS technology was first described in 1996 [[2]Risch N. Merikangas K. The future of genetic studies of complex human diseases.Science. 1996; 5281: 1516-1517Crossref Google Scholar] (Box 1), its main limitations were due to the lack of technology and the authors suggested geneticists to keep their samples for future experiments. Originally, the HapMap project characterized the pattern of genetic variations in 270 individuals of different ethnicities. The dataset then amounted to a total of 3.1 million SNPs, which is a very important resource for the selection of genetic markers and genotyping assays. GWAS involves identification of statistical associations between a trait or disease and a genetic polymorphism (SNP), throughout the entire genome. Linkage disequilibrium can be used to indirectly determine untyped variations around an SNP. The r2 value, which is commonly used to evaluate linkage disequilibriums, measures the correlation between alleles at a nearby genetic variant. If alleles of 2 SNPs are always found on the same chromosome, there is a perfect correlation and r2 = 1. In practice, this means that typing one of these 2 SNPs will provide complete allele information at the 2 sites. If r2 <1 between the 2 alleles, the sample size will need to be proportionally increased to detect a significant association [[3]Karlsen T.H. Melum E. Franke A. The utility of genome-wide association studies in hepatology.Hepatology. 2010; 5: 1833-1842Crossref Scopus (23) Google Scholar]. So far only SNPs with a frequency of more than 5% of the minor allele can be detected effectively by linkage disequilibrium in GWAS. Thus, the HapMAp project does not provide perfect coverage of GWAS so that even in very large GWAS it is impossible to detect rare low frequency genetic variants. However, the technology will probably improve in the future, thus increasing coverage of low frequency variants. Different methods of correcting the p values of associations have been described to counteract associations due to chance because of the many statistical tests. The most commonly used approach consists in the adjustment of the p value according to Bonferroni. The threshold of 0.05 is divided by the number of SNPs analyzed, which leads to an adjusted threshold of 10−6 to 10−8, for current available assays. However, several real associations may be lost by deleting all associations with a p value above this threshold. Furthermore, to improve the statistical relevance of GWAS, it is extremely important to replicate significant associations in at least one independent cohort of individuals (trait and control). The GWAS technology has greatly improved in the last decade, however, the detection of rare variants would probably improve this approach even more [[3]Karlsen T.H. Melum E. Franke A. The utility of genome-wide association studies in hepatology.Hepatology. 2010; 5: 1833-1842Crossref Scopus (23) Google Scholar]. Liver fibrosis is defined as the excess accumulation of extracellular matrix proteins. Fibrogenesis is a complex dynamic process, mediated by necro-inflammation, and activation of stellate cells [[4]Marcellin P. Asselah T. Boyer N. Fibrosis and disease progression in hepatitis C.Hepatology. 2002; 5: S47-S56Crossref Google Scholar]. Fibrosis progression determines the prognosis and thus the need for treatment. It is therefore crucial to monitor fibrosis in patients with CHC. Several studies have assessed the identification of mRNAs and miRNAs expression during fibrosis (Table 1) and will be discussed in the first part of the review.Table 1Variations in mRNAs and miRNAs expression associated with fibrosis progression. (A) Markers identified by candidate gene strategy; (B) markers identified by scanning approach. Open table in a new tab The natural history of HCV and factors associated with fibrosis progression are discussed in Box 2. A deregulation of gene expression mainly affecting the IFN αβ and γ pathways (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1, CXCL9, CXCL10, CXCL11, and Viperin) has been reported in patients with CHC and mild fibrosis [5Bieche I. Asselah T. Laurendeau I. Vidaud D. Degot C. Paradis V. et al.Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection.Virology. 2005; 1: 130-144Crossref Scopus (94) Google Scholar, 6Helbig K.J. Lau D.T. Semendric L. Harley H.A. Beard M.R. Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector.Hepatology. 2005; 3: 702-710Crossref Scopus (121) Google Scholar]. The transition from mild to moderate fibrosis is crucial in the decision to treat. The expression of 240 liver genes has been compared in 62 patients with mild fibrosis (F1) and moderate fibrosis (F2). Twenty-two genes were upregulated in F2 and mainly involved the cytoskeleton, growth factor cytokines, growth factor receptors, extra-cellular matrix remodeling, and the cell junction [[7]Asselah T. Bieche I. Laurendeau I. Paradis V. Vidaud D. Degott C. et al.Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C.Gastroenterology. 2005; 6: 2064-2075Abstract Full Text Full Text PDF Scopus (93) Google Scholar]. Liver steatosis is frequent in patients with CHC [[8]Asselah T. Rubbia-Brandt L. Marcellin P. Negro F. Steatosis in chronic hepatitis C: why does it really matter?.Gut. 2006; 1: 123-130Crossref Scopus (224) Google Scholar]. Three genes involved in the inflammatory pathway (SITPEC, SIGIRR, and TOLLIP) have been described as specifically associated with advanced steatosis in CHC [[9]Chiappini F. Barrier A. Saffroy R. Domart M.C. Dagues N. Azoulay D. et al.Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray.Lab Invest. 2006; 2: 154-165Crossref Scopus (39) Google Scholar]. One study investigated changes in liver mRNAs expression in 13 transplanted patients comparing patients in whom fibrosis progressed with those in whom it did not, before and after transplantation [[10]Smith M.W. Walters K.A. Korth M.J. Fitzgibbon M. Proll S. Thompson J.C. et al.Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients.Gastroenterology. 2006; 1: 179-187Abstract Full Text Full Text PDF Scopus (62) Google Scholar]. Fifteen of the 31 upregulated genes encoded for markers of myofibroblasts and myofibroblast-like cells. Liver stress injury and fibrosis development can cause an increase in myofibroblasts due to activation of HSCs and their conversion into the contractile phenotype [[10]Smith M.W. Walters K.A. Korth M.J. Fitzgibbon M. Proll S. Thompson J.C. et al.Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients.Gastroenterology. 2006; 1: 179-187Abstract Full Text Full Text PDF Scopus (62) Google Scholar]. It is interesting to note that these data suggest that early fibrosis progression may be associated with a reduction in the pools of quiescent HSCs and with an increase in the number of myofibroblast-like cells. Micro-RNAs regulate up to 60% of cellular mRNA expression and stability [11Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 2: 281-297Abstract Full Text Full Text PDF Scopus (8057) Google Scholar, 12Meister G. Landthaler M. Dorsett Y. Tuschl T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing.RNA. 2004; 3: 544-550Crossref Scopus (330) Google Scholar, 13Meister G. Tuschl T. Mechanisms of gene silencing by double-stranded RNA.Nature. 2004; 7006: 343-349Crossref Scopus (1058) Google Scholar, 14Napoli C. Lemieux C. Jorgensen R. Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans.Plant Cell. 1990; 4: 279-289Crossref Google Scholar]. In one study, mir-21 expression was found to be correlated to both HCV viral load and fibrosis [[15]Marquez R.T. Bandyopadhyay S. Wendlandt E.B. Keck K. Hoffer B.A. Icardi M.S. et al.Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans.Lab Invest. 2010; 12: 1727-1736Crossref Scopus (42) Google Scholar]. Results are conflicting for mir-122 but it is probably only weakly or not associated with viral load [15Marquez R.T. Bandyopadhyay S. Wendlandt E.B. Keck K. Hoffer B.A. Icardi M.S. et al.Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans.Lab Invest. 2010; 12: 1727-1736Crossref Scopus (42) Google Scholar, 16Morita K. Taketomi A. Shirabe K. Umeda K. Kayashima H. Ninomiya M. et al.Clinical significance and potential of hepatic microRNA-122 expression in hepatitis C.Liver Int. 2011; 4: 474-484Crossref Scopus (24) Google Scholar]. Two studies have reported a correlation between mir-122 expression, liver damage, and stages of fibrosis [15Marquez R.T. Bandyopadhyay S. Wendlandt E.B. Keck K. Hoffer B.A. Icardi M.S. et al.Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans.Lab Invest. 2010; 12: 1727-1736Crossref Scopus (42) Google Scholar, 16Morita K. Taketomi A. Shirabe K. Umeda K. Kayashima H. Ninomiya M. et al.Clinical significance and potential of hepatic microRNA-122 expression in hepatitis C.Liver Int. 2011; 4: 474-484Crossref Scopus (24) Google Scholar] while another did not find any association with mir-122 expression in the serum of patients with CHC [[17]Bihrer V. Friedrich-Rust M. Kronenberger B. Forestier N. Haupenthal J. Shi Y. et al.Serum miR-122 as a Biomarker of Necroinflammation in Patients With Chronic Hepatitis C Virus Infection.Am J Gastroenterol. 2011; 109: 1163-1669Google Scholar]. A recent study demonstrated that the different members of the mir-29 family were all downregulated in HCV infected patients. Moreover, freshly isolated HSCs expressed a high rate of mir-29, which was rapidly and markedly reduced after HSC activation [[18]Bandyopadhyay S. Friedman R.C. Marquez R.T. Keck K. Kong B. Icardi M.S. et al.Hepatitis C virus infection and hepatic stellate cell activation downregulate miR-29: miR-29 overexpression reduces hepatitis C viral abundance in culture.J Infect Dis. 2011; 12: 1753-1762Crossref Scopus (15) Google Scholar]. Mir-29 targeted various types of collagen and, interestingly, mir-29 inhibition in mice has been shown to upregulate collagen expression in the liver [[19]van Rooij E. Sutherland L.B. Thatcher J.E. DiMaio J.M. Naseem R.H. Marshall W.S. et al.Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.Proc Natl Acad Sci USA. 2008; 35: 13027-13032Crossref Scopus (394) Google Scholar]. Thus, mir-29 downregulation during HSCs activation might play a role in fibrosis by inducing direct accumulation of collagen in the liver. Several studies have tried to indentify SNPs associated with either fibrosis progression or treatment response (Table 2).Table 2Identification of SNPs associated with fibrosis and the response to antivirals in patients with chronic hepatitis C. Open table in a new tab Matrix metalloproteinases (MMPs) play an important role in fibrosis progression. MMP-1, MMP-3, and MMP-9 gene polymorphisms have been shown to influence the transcriptional activity of their respective gene promoters. Interestingly, both MMP-1 2G homozygote and MMP-9 C allele were more frequent in HCV patients with cirrhosis than in those without cirrhosis [[20]Okamoto K. Mimura K. Murawaki Y. Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease.J Gastroenterol Hepatol. 2005; 7: 1102-1108Crossref Google Scholar]. Monocyte chemotactic protein 1 (MCP-1) is upregulated in HSCs during CHC. MCP-1 harbors a functional polymorphism located in its promoter. Interestingly, the 2A homozygote genotype in this specific polymorphism was more frequent in patients with mild fibrosis [[21]Muhlbauer M. Bosserhoff A.K. Hartmann A. Thasler W.E. Weiss T.S. Herfarth H. et al.A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.Gastroenterology. 2003; 4: 1085-1093Abstract Full Text Full Text PDF Scopus (121) Google Scholar]. Decreased vitamin D levels and genetic variations in the vitamin D receptor (VDR) gene have been described as an important modulator of multiple diseases, including hepatic disorders [[22]Valdivielso J.M. Fernandez E. Vitamin D receptor polymorphisms and diseases.Clin Chim Acta. 2006; 1–2: 1-12Crossref Scopus (139) Google Scholar]. VDR genotyping in 251 patients with chronic hepatitis C showed an association between the haplotype rs1544410 C, rs7975232 A, and rs731236 A with fibrosis progression and cirrhosis. Forty-five percent of the [CCA]-haplotype patients had rapid fibrosis progression and 21.1% had cirrhosis [[23]Baur K. Mertens J.C. Schmitt J. Iwata R. Stieger B. Eloranta J.J. et al.Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1I1) variants on fibrosis progression rate in HCV patients.Liver Int. 2011; 32: 635-643Crossref PubMed Scopus (17) Google Scholar]. A gene-centric disease association study of 24, 832 putative functional SNPs was performed to assess the association of SNPs with cirrhosis in a cohort of 433 patients with CHC [[24]Huang H. Shiffman M.L. Cheung R.C. Layden T.J. Friedman S. Abar O.T. et al.Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.Gastroenterology. 2006; 6: 1679-1687Abstract Full Text Full Text PDF Scopus (73) Google Scholar]. One SNP located in the DEAD box polypeptide 5 was associated with an increased risk of advanced fibrosis while the second SNP, located in the gene encoding carnitine palmitoyltransferase 1A (CPTA1), was associated with a decreased risk of advanced fibrosis [[24]Huang H. Shiffman M.L. Cheung R.C. Layden T.J. Friedman S. Abar O.T. et al.Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.Gastroenterology. 2006; 6: 1679-1687Abstract Full Text Full Text PDF Scopus (73) Google Scholar]. In a second study, the authors confirmed all significant SNPs, and selected 361 markers to build a signature predicting cirrhosis, called the cirrhosis risk score (CRS) [[25]Huang H. Shiffman M.L. Friedman S. Venkatesh R. Bzowej N. Abar O.T. et al.A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.Hepatology. 2007; 2: 297-306Crossref Scopus (132) Google Scholar]. Interestingly, DDX5 and CPT1A were not selected for the final 7 SNPs for the CRS. Possible reasons were (i) lower odds ratios and frequencies in the risk group and (ii) decreased robustness and accuracy of these 2 SNPs in multivariate analysis compared to the 7 selected genes. Of the 7 CRS genes, antizyme-inhibitor-1 (AZIN1) and Toll-like receptor 4 (TLR4) have been shown to play a role in fibrosis. A recent study has reported that the association of AZIN1 SNP with the rapid progression of fibrosis, leads to enhanced generation of a novel alternative splice form from AZIN1 that modifies the fibrogenic potential of HSCs [[26]Paris A.J. Snapir Z. Christopherson C.D. Kwok S.Y. Lee U.E. Ghiassi-Nejad Z. et al.A polymorphism that delays fibrosis in hepatitis C promotes alternative splicing of AZIN1, reducing fibrogenesis.Hepatology. 2011; 54: 2198-2207Crossref PubMed Scopus (10) Google Scholar]. All 7 SNPs were associated with the risk of cirrhosis with odds ratios ranging from 1.86 to 3.23. However, the AUC of each SNP was <0.6, showing that predictability was moderate when they were used individually [[25]Huang H. Shiffman M.L. Friedman S. Venkatesh R. Bzowej N. Abar O.T. et al.A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.Hepatology. 2007; 2: 297-306Crossref Scopus (132) Google Scholar]. The addition of clinical factors to the group of SNPs or each of them individually did not significantly improve the AUC. Two major limitations are associated with the use of CRS to identify patients with rapid progression of fibrosis: (i) CRS cut-off values may only distinguish patients with a very high risk of cirrhosis (ii) CRS was identified in Caucasian patients so it may not be applicable to all ethnic groups [[25]Huang H. Shiffman M.L. Friedman S. Venkatesh R. Bzowej N. Abar O.T. et al.A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.Hepatology. 2007; 2: 297-306Crossref Scopus (132) Google Scholar]. In another study, paired liver biopsies from 271 untreated patients with CHC (F0 = 104, F1 = 101, and F2 = 59) were followed-up for at least 60 months. Mean CRS was significantly higher is patients in whom fibrosis progressed, especially in patients with F0 at the initial biopsy [[27]Marcolongo M. Young B. Dal Pero F. Fattovich G. Peraro L. Guido M. et al.A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C.Hepatology. 2009; 4: 1038-1044Crossref Scopus (53) Google Scholar]. CRS remained the only variable associated with fibrosis progression in multivariate analysis, including gender and alcohol intake [[28]Trepo E. Potthoff A. Pradat P. Bakshi R. Young B. Lagier R. et al.Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease.J Hepatol. 2011; 1: 38-44Abstract Full Text Full Text PDF Scopus (14) Google Scholar]. Genetic studies have reported an association between advanced steatosis and specific SNPs located in genes encoding microsomal triglyceride transfer protein (MTP G493T) [29Petit J.M. Masson D. Minello A. Duvillard L. Galland F. Verges B. et al.Lack of association between microsomal triglyceride transfer protein gene polymorphism and liver steatosis in HCV-infected patients.Mol Genet Metab. 2006; 2: 196-198Abstract Full Text Full Text PDF Scopus (9) Google Scholar, 30Zampino R. Ingrosso D. Durante-Mangoni E. Capasso R. Tripodi M.F. Restivo L. et al.Microsomal triglyceride transfer protein (MTP) −493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients.J Viral Hepat. 2008; 10: 740-746Crossref Scopus (18) Google Scholar, 31Mirandola S. Osterreicher C.H. Marcolongo M. Datz C. Aigner E. Schlabrakowski A. et al.Microsomal triglyceride transfer protein polymorphism (−493G/T) is associated with hepatic steatosis in patients with chronic hepatitis C.Liver Int. 2009; 4: 557-565Crossref Scopus (11) Google Scholar], peroxisome proliferator activated alpha (PPAR L162V) [[32]Verdi H. Koytak E.S. Onder O. Ergul A.A. Cinar K. Idilman R. et al.Peroxisome proliferator-activated receptor alpha L162V polymorphism in nonalcoholic steatohepatitis and genotype 1 hepatitis C virus-related liver steatosis.J Investig Med. 2005; 7: 353-359Crossref Google Scholar], methylenetetrahydrofolate reductase (MTHFR C677T) [33Adinolfi L.E. Ingrosso D. Cesaro G. Cimmino A. D’Anto M. Capasso R. et al.Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients.Hepatology. 2005; 5: 995-1003Crossref Scopus (79) Google Scholar, 34Borgia G. Gentile I. Fortunato G. Borrelli F. Borelli S. de Caterina M. et al.Homocysteine levels and sustained virological response to pegylated-interferon alpha2b plus ribavirin therapy for chronic hepatitis C: a prospective study.Liver Int. 2009; 2: 248-252Crossref Scopus (12) Google Scholar], cytokines playing a role in the inflammatory response such as interlekin-10 and -6 (IL-10 and IL-6) [[35]Iuliano A.D. Feingold E. Wahed A.S. Kleiner D.E. Belle S.H. Conjeevaram H.S. et al.Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.Intervirology. 2009; 1: 49-56Crossref Scopus (5) Google Scholar], transforming growth factor beta-1 (TGFB1) [[35]Iuliano A.D. Feingold E. Wahed A.S. Kleiner D.E. Belle S.H. Conjeevaram H.S. et al.Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.Intervirology. 2009; 1: 49-56Crossref Scopus (5) Google Scholar], tumor necrosis factor (TNF, −238 position) [36Sanchez-Munoz D. Romero-Gomez M. Gonzalez-Escribano M.F. Torres B. Castellano-Megias V.M. Gomez-Izquierdo L. et al.Tumour necrosis factor alpha polymorphisms are not involved in the development of steatosis in chronic hepatitis C.Eur J Gastroenterol Hepatol. 2004; 8: 761-765Crossref Scopus (6) Google Scholar, 37Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2005; 4: 1209-1217Google Scholar] and leptin receptor (LEPR) [[35]Iuliano A.D. Feingold E. Wahed A.S. Kleiner D.E. Belle S.H. Conjeevaram H.S. et al.Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.Intervirology. 2009; 1: 49-56Crossref Scopus (5) Google Scholar]. A non-synonymous sequence variation (rs738409 C/G) encoding an isoleucine to methionine substitution in the adiponutrin/patatin-like phospholipase-3 (PNPLA3) has been shown to be strongly associated with increased hepatic fat levels [[38]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 12: 1461-1465Crossref Scopus (404) Google Scholar]. This SNP was then shown to be associated with disease severity, fibrosis, and steatosis in non-alcoholic fatty liver disease (NAFLD) [39Rotman Y. Koh C. Zmuda J.M. Kleiner D.E. Liang T.J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Hepatology. 2010; 3: 894-903Crossref Scopus (83) Google Scholar, 40Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 4: 1209-1217Crossref Scopus (116) Google Scholar] and in alcoholic liver disease (ALD). Moreover, the same SNP was also associated with elevated liver enzymes in healthy subjects [[41]Kollerits B. Coassin S. Kiechl S. Hunt S.C. Paulweber B. Willeit J. et al.A common variant in the adiponutrin gene influences liver enzyme values.J Med Genet. 2010; 2: 116-119Crossref Scopus (23) Google Scholar]. Interestingly, patients with CHC carrying the rs738409 mutant GG allele had a high risk of steatosis as well as fibrosis and fibrosis progression [42Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat Genet. 2010; 1: 21-23Crossref Scopus (97) Google Scholar, 43Trepo E. Pradat P. Potthoff A. Momozawa Y. Quertinmont E. Gustot T. et al.Impact of patatin-like phospholipase-3 (rs738409 C > G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.Hepatology. 2011; 1: 60-69Crossref Scopus (37) Google Scholar, 44Stickel F. Buch S. Lau K. Zu Schwabedissen H.M. Berg T. Ridinger M. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians.Hepatology. 2011; 1: 86-95Crossref Scopus (54) Google Scholar]. However, there are conflicting results reporting that PNPLA3 rs738409 GG mutant variant may be a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects were negligible in patients with HCV cirrhosis [[45]Nischalke H.D. Berger C. Luda C. Berg T. Muller T. Grunhage F. et al.The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.PLoS One. 2011; 11: e27087Crossref Scopus (13) Google Scholar]. The analysis of rs8099917 SNPs during liver fibrosis in chronic hepatitis C" @default.
• W2034641100 created "2016-06-24" @default.
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• W2034641100 date "2012-11-01" @default.
• W2034641100 modified "2023-10-01" @default.
• W2034641100 title "Genomics and HCV infection: Progression of fibrosis and treatment response" @default.
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