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• W2076337612 abstract "Chronic hepatitis C virus (HCV) infection represents a major health problem worldwide and is associated with increased morbidity and mortality (1). Although cohort studies clearly show that patients with chronic HCV infection are at increased risk for development of cirrhosis, the 20-year rates of progression to cirrhosis have been reported to range from 5 to 20% in several cohort studies (1). In any case, the majority of chronic HCV patients will not develop cirrhosis, at least within the first 20–30 years of infection. More rapid and/or more frequent progression to cirrhosis has been associated with older age, older age at acute infection, alcohol abuse, hepatitis B or human immunodeficiency virus coinfection, immunosuppression, diabetes mellitus, metabolic syndrome or severe hepatic steatosis (1, 2). However, the absolute risk of cirrhosis varies substantially and cannot be predicted for every individual patient. Therefore, the effects of host genetic factors on the fibrosis progression rate have been sought. Over the past years, there is increasing evidence that genetic factors influence the natural history of chronic HCV infection (3, 4). In particular, several single nucleotide polymorphisms (SNPs), which are single nucleotide variations at specific positions of the genome detected in >1% of the population, have been associated with the rate of fibrosis progression, the risk for hepatocellular carcinoma and/or the response to therapy (3, 4). Because immune and inflammatory response has a key role in the development of liver injury, genomic scan for SNPs in the genes of several important inflammatory mediators was a reasonable initial approach. The progression rate of liver fibrosis in patients with chronic hepatitis C has been reported to be influenced by SNPs at positions +874 (T-to-A) of the interferon (IFN)-γ gene (5), −308 (G-to-A) of the promoter region of the tumour necrosis factor-α gene (6), 46 (Q-to-K) of the monocyte chemotactic protein 2 gene (7), and −1082 (AA genotype and ATA/ATA and ACC/ACC homozygous haplotypes) and −819 (C-to-A) of interleukin-10 (IL-10) gene (8, 9). In addition, polymorphisms resulting in an amino acid change in exon 8 of the low-density lipoprotein receptor as well as the presence of factor V Leiden polymorphism have also been associated with more rapid progression of fibrosis in chronic hepatitis C (10, 11). It should be noted, however, that all previous studies have limited the analysis to one gene or to a small number of candidate genes, and their findings have not been validated in independent cohorts of chronic hepatitis C patients. In a more extensive recent study, Huang et al. (12) tried to identify clinically significant SNPs in 433 patients with chronic hepatitis C through a genome-wide scan and to validate their findings in a separate cohort of 483 patients. They carried out a genome scan consisting of 24 823 SNPs (68.3% coding functional SNPs, 24.9% noncoding putative regulatory SNPs and 6.8% other types of SNPs) covering 12 248 genes. Interestingly, among the first 100 SNPs associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis) in the first group, only two were found to be significantly associated with advanced fibrosis. This was also the case in the second cohort. A missense SNP in the DEAD (Asp–Glu–Ala–Asp) box polypeptide 5 gene causing an amino acid replacement at position 480 (S480A) in exon XIII was associated with an increased risk of advanced fibrosis [odds ratio (OR): 1.8 and 2.3 in the two cohorts], while a missense SNP in the carnitine palmitoyltransferase 1A gene causing an amino acid change at position 275 (A275T) in exon VIII was associated with a decreased risk for advanced fibrosis (OR: 0.3 and 0.6 in the two cohorts). Subsequently, Huang et al. (13) tried to develop a cirrhosis risk score (CRS) based on genetic markers identified from two Caucasian patients similar to the previous cohorts. Among 361 SNPs showing similarly significant associations with liver fibrosis in the two cohorts, seven SNPs (one SNP in the antizyme-inhibitor-1 gene, one SNP in the Toll-like receptor-4 gene and five SNPs in five other genes of unclear function) with the highest predictability for cirrhosis (OR: 1.86–3.23) were used to build the CRS signature. CRS offered a better prediction of cirrhosis compared with clinical factors (age, gender and alcohol abuse): area –under the receiver operating characteristic curves 0.73–0.75 for CRS, 0.53 for clinical factors and 0.76 for CRS and clinical factors together. Two cut-off CRS values (range: 0–1) were eventually suggested to potentially identify the majority of low-risk (<0.50) and high-risk (>0.70) patients for development of cirrhosis. In this issue of the Journal, Kato et al. (14) report another genetic factor associated with an increased risk of cirrhosis in Japanese patients with chronic hepatitis C. Using Taqman allelic discrimination and sequencing technique, they studied nine SNPs of the interferon regulatory factor 7 (IRF-7) gene (four SNPs in the promoter region) in 406 patients (178 with cirrhosis). There were two nonsynonymous SNPs at positions 1047 and 2157 (A-to-G in both cases) resulting in amino acid changes (Lys/Glu and Gln/Arg respectively). SNP1047AG and SNP2157AG genotypes (compared with AA; there was no case with genotype GG), which were in complete linkage disequilibrium, were detected significantly more frequently in cirrhotic (5.6%) than in noncirrhotic patients (1.7%) [OR: 3.27; 95% confidence interval (CI): 1.02–10.5; P=0.03]. There was no association between SNPs in the promoter region and presence of cirrhosis. In multivariate analysis, SNP1047AG and SNP2157AG were independently associated with cirrhosis (AA vs AG- adjusted OR: 2.5; 95% CI: 1.2–5.6; P=0.02). One common methodological limitation of genetic epidemiological studies is the evaluation of alleles with unclear functional significance (3). However, such a limitation did not exist for this study, because IRF-7 has been clearly found to affect immune responses mainly by regulating the transcription of IFN-α genes (15). IFNs represent one of the important initial defence mechanisms against many viral infections (16). IRF-7 has a key role in the regulation of type I IFN response through a positive feedback that amplifies IFN production and eventually antiviral action (17). In particular, IFN-I, which is produced as an initial response to viral antigens, induces the transcription of the IRF-7 gene, and then IRF-7 activates the promoter of IFN-α genes (16). Additional possible mechanisms for the effect of IRF-7 gene polymorphisms on the progression of liver fibrosis include the IRF-7-induced activation of IFN-β, regulated on activation normal T cell expressed and secreted (RANTES) and several other genes including genes involved in signal transduction, transcriptional activation and apoptosis (7, 18). In fact, the activation of RANTES has been shown to play an important role in the progression of fibrosis. SNP in the RANTES gene was reported to affect the hepatic inflammation in chronic HCV patients (7, 19). Of course, polymorphisms of a gene may not always affect the function (quality and/or quantity) of the gene product. To clarify this issue, the authors performed functional analysis of SNP1047 and SNP2157 by transcriptional activation of the IFN-α promoter (14). Using an IFN-α promoter luciferase activity assay, they observed that SNP1047G/SNP2157G compared with SNP1047A/SNP2157A, was associated with significantly higher luciferase activity (40–70- and 90–130-fold higher for the promoter of IFN-α2 and IFN-α4 plasmids, P=0.0001 and 0.008 respectively). Because an A-to-G substitution at any of these two positions results in significantly higher expression of IFN-α, the SNPs evaluated in this study seem to alter the function of the IRF-7 gene. The current study provides an additional step in the right direction for the identification of genetic markers that will predict the risk for cirrhosis in chronic HCV patients. Despite its careful design, however, several issues on the roles of SNPs in the IRF-7 gene and of other host genetic factors remain unaddressed and may remain unclear for some years. Firstly, although these data support an effect of the IRF-7 nonsynonymous SNPs on the risk of cirrhosis, only a minority of Japanese patients had such SNPs. Thus, other host factors may be responsible in >90% of chronic HCV Japanese patients who develop cirrhosis. Moreover, SNPs may differ among different patient populations and therefore their role should also be evaluated and validated in other chronic HCV patient groups. In fact, contradictory results have been reported from different studies evaluating the significance of polymorphisms at the same position of a gene, such as the −1082 position of the IL-10 gene (8, 9). Finally, it should always be kept in mind that the development and progression of hepatic fibrosis in chronic liver diseases is most probably affected by multiple genes, several environmental factors and the specific characteristics of the cause of liver injury. Not all HCV strains may cause the same severity of fibrosis to the one patient and neither may all patients infected with an identical HCV strain have the same rate of fibrosis progression. Because almost all SNPs that have been found to influence the progression of fibrosis to date had moderate ORs, multiple (>10) genetic markers with at least medium prevalence in a population are required to achieve appreciable predictability for cirrhosis (20). Thus, all candidate genetic markers of fibrosis progression or of cirrhosis development should be studied in several large cohorts of patients together with environmental and viral factors that may affect the natural course of chronic HCV infection." @default.
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• W2076337612 title "Role of genetic polymorphisms in the progression of liver fibrosis in chronic hepatitis C virus infection" @default.
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