Identification of Two Gene Variants Associated With Risk of Advanced Fibrosis in Patients With Chronic Hepatitis C

doi:10.1053/j.gastro.2006.02.032

Gastroenterology

Volume 130, Issue 6, May 2006, Pages 1679-1687

https://doi.org/10.1053/j.gastro.2006.02.032 Get rights and content

Background & Aims: Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC. Methods: A total of 916 subjects with CHC was enrolled from 2 centers. A gene-centric disease association study of 24,832 putative functional, single nucleotide polymorphisms (SNPs) was performed. Of the 1609 SNPs that were significantly associated (P ≤ .05) with advanced fibrosis in the discovery cohort (University of California San Francisco [UCSF], N = 433), the first batch of 100 SNPs were selected for validation in the replication cohort (Virginia Commonwealth University [VCU], N = 483). Results: A missense SNP in the DEAD box polypeptide 5 (DDX5) gene was significantly associated with an increased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 1.8 and 2.2, respectively). Two diplotype groups, carrying the haplotypes composed of the DDX5 SNP and 2 neighboring POLG2 SNPs were also significantly associated with an increased risk of advanced fibrosis and had comparable or better risk estimates. In addition, a missense SNP in the carnitine palmitoyltransferase 1A (CPT1A) gene was associated with a decreased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 0.3 and 0.6, respectively). Conclusions: Subjects with CHC carrying DDX5 minor allele or DDX5-POLG2 haplotypes are at an increased risk of developing advanced fibrosis, whereas those carrying the CPT1A minor allele are at a decreased risk.

Section snippets

Study Population

A total of 916 patients with well-documented chronic HCV were prospectively recruited from the hepatology clinics at 2 large centers, the University of California San Francisco (UCSF; N = 433) and the Virginia Commonwealth University Medical Center (VCU; N = 483), over a 22 consecutive month period. Patients were either new referrals for evaluation and/or treatment of chronic HCV or existing patients being monitored on an ongoing basis at either of these centers. All patients were adults (ages,

Study Subjects

Clinical characteristics of the 2 patient populations are listed in Table 1. The 2 cohorts shared many similarities, suggesting that there was a good cross-sectional representation of HCV patients. The mean age and the proportion of white subjects within the 2 groups were similar. A higher proportion of patients from UCSF were male, and these patients had consumed more alcohol than the patients at VCU. Despite this, the mean fibrosis score and the percentage of patients with advanced fibrosis

Discussion

Although some HCV patients develop progressive fibrosis and cirrhosis, many patients have mild liver disease for decades and have no morbidity or mortality that could be attributed to HCV infection.²³ The most recent NIH Consensus Conference recommended that all HCV patients could be considered for therapy regardless of serum alanine aminotransferase and degree of fibrosis.² Unfortunately, such an approach exposes many patients with mild disease to the adverse events and high cost associated

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Host genetic polymorphisms influence the fibrosis progression of chronic hepatitis C (CHC) patients. Previous studies have shown the association of human platelet antigens (HPAs) polymorphisms with CHC. However, little is known regarding the association of HPAs polymorphisms with the fibrosis progression of CHC. The aim of this study was to determine the association of HPA -2, -3, -5 and -15 polymorphisms with the levels of serum fibrosis marks in CHC patients.
The HPA -2, -3, -5 and -15 were genotyped by 5ˊ-nuclease assay in 211 CHC patients, while the serum concentration of hyaluronic acid (HA), collagen IV (CIV), amino-terminal pro-peptide of type III procollagen (PIIINP), and laminin (LN) from the same samples were measured by time resolved fluorescence immunoassay.
The level of serum LN was significantly lower in CHC patients with HPA-15aa genotype compared to those with HPA-15ab/bb (P = 0.032) but did not differ among HPA-2, -3 and -5 genotypes. There were no difference in HA, CIV and PIIINP levels among HPA-2, -3,-5 and -15 genotypes.
This study demonstrates that HPA-15 aa polymorphism is associated lower serum LN in CHC, which suggests that HPA -15 aa may be involved in the fibrosis progression of CHC.
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Liver fibrosis results from a wound healing response to chronic injury, which leads to excessive matrix deposition. Genome wide association studies have showen transcriptional dysregulation in mild and severe liver fibrosis. Recent studies suggested that genetic markers may be able to define the exact stage of liver fibrosis.
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The study was performed on 105 treatment naïve HCV genotype 4 infected patients [F0–F2, n = 56; F3–F4, n = 49] and 16 healthy subjects. The study included PCR array on 84 fibrosis related genes followed by customization of a smaller array consisting of 11 genes that were designed on the bases of results obtained from the larger array. Genes that displayed significant dysregulation at mRNA levels were validated at protein levels.
Two major pathways exhibited high dysregulation in early fibrosis as compared with controls or when compared with late fibrosis, these were the TGFβ - related pathway genes and Matrix - deposition associated genes. Hepatic stellate cell (HSC) activators i.e. TGFβ pathway genes [TGFβ1, 2 and 3, their receptors TGFβR1 and 2, signaling molecules SMAD genes and PDGF growth factors] were considerably over-expressed at transcriptional levels as early as F0, whereas expression of their inhibitor TGIF1 was simultaneously down regulated. Matrix proteins including collagen and MMPs were upregulated in early fibrosis whereas tissue inhibitors TIMPs 1 and 2 began over expression in late fibrosis. Expression at protein levels was concordant with RNA data excluding dysregulation at post transcriptional levels.
Since these 2 gene sets are closely interrelated regarding HSC activation and proliferation, we assume that the current findings suggest that they are favorable targets to further search for stage specific markers.
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Liver diseases are a cause of global morbidity and mortality. While the predominance of specific liver diseases varies with geographical location, the diversity of hepatic diseases affecting the underdeveloped, developing, and developed countries is high, with diseases ranging from infectious diseases of the liver to neoplasia and obesity-related illnesses. This chapter will discuss progress made toward an improved understanding of the cellular and molecular basis of various aspects of liver pathophysiology, including the processes of hepatic development, metabolic zonation, and liver regeneration. Equally relevant to this review is recent progress toward elucidation of basic mechanisms that lead from hepatic injury and inflammation to hepatic fibrosis and cirrhosis. Furthermore, there has been a notable improvement in our understanding of cellular and molecular aberrations in liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease, and both benign and malignant tumors of the liver, in the hope of improving diagnostic, prognostic, and therapeutic tools. In this chapter, we concisely discuss fundamental concepts in hepatic pathobiology, with emphasis on cellular and molecular mechanisms, summarizing the biological and translational significance of such concepts.
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DEAH-box helicase 33 (DHX33) has been implicated in ribosome biogenesis, mRNA translation and inflammation. However, the role of DHX33 in human cancer is rarely studied. Here, we showed that DHX33 expression was significantly increased in hepatocellular carcinoma (HCC), compared with the adjacent nontumorous tissues. In a cohort of 520 patients, DHX33 expression in HCC was closely associated with tumor size (P = 0.007), serum AFP level (P = 0.011), and tumor capsule (P = 0.030). Kaplan–Meier analysis indicated high DHX33 expression was correlated with worse overall and disease-free survival, and higher recurrence rate. The prognostic value of DHX33 was further confirmed by stratified survival analysis. Multivariate analysis revealed DHX33 as an independent prognostic factor for poor overall survival (Hazard Ratio = 1.772, 95% confident interval: 1.451–2.165, P < 0.0001). Our data therefore suggest DHX33 is overexpressed in HCC and serves as a promising prognostic biomarker for this deadly disease.

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: Supported by Celera Diagnostics.

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Clinical–liver, pancreas, and biliary tractIdentification of Two Gene Variants Associated With Risk of Advanced Fibrosis in Patients With Chronic Hepatitis C

Section snippets

Study Population

Study Subjects

Discussion

Lancet

Hepatology

Genet Med

Lancet

Am J Hum Genet

Am J Gastroenterol

Hepatology

Gastroenterology

J Biol Chem

J Biol Chem

Mol Aspects Med

J Biol Chem

Management of hepatitis CJune 10–12, 2002

Hepatology

AASLD practice guidelinediagnosis, management, and treatment of hepatitis C

Hepatology

Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infectiona cross-sectional and longitudinal study

Gut

Hepatitis C and nonalcoholic fatty liver disease

Semin Liver Dis

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease

Nat Genet

Searching for genetic determinants in the new millennium

Nature

Clinical–liver, pancreas, and biliary tract
Identification of Two Gene Variants Associated With Risk of Advanced Fibrosis in Patients With Chronic Hepatitis C