Abstract
BackgroundOur previous study indicated that a common variant (rs430397 G>A) in the intron 5 of glucose-regulated protein 78 (GRP78) gene was associated with risk and prognosis of primary hepatocellular carcinoma (HCC), including HBV- and cirrhosis-related HCC. rs430397 polymorphism may be a contributing factor or biomarker of HBV infection or HBV-related cirrhosis.Methodology/Principal Findings539 non-HBV-infected individuals, 205 self-limited infection and 496 persistent HBV infection were recruited between January 2001 and April 2005 from the hospitals in Southern China. Genomic DNA was genotyped for rs430397. The associations between the variation and susceptibility to liver cirrhosis (LC) in persistent HBV infection were examined. We observed that individuals carrying allele rs430397A were more likely to become HBV-related LC. When persistently infected patients were divided into four subgroups, patients with phase IV had an increased allele A and genotype AG compared with phase I and/or phase III. Decreased serum albumin and prolonged plasma prothrombin time (PT) were showed in LC patients carrying genotype AA. Furthermore, rs430397 genotype had an increased susceptibility to LC with dose-dependent manners (P-trend = 0.005), and the genotype did constitute a risk factor for the development of advanced LC (Child–Pugh classification C and B, P-trend = 0.021).Conclusions/Significancers430397 polymorphism may be a contributing factor to LC in persistent HBV carriers.
Highlights
Hepatitis B, called serum hepatitis, is a global health problem that affects more than 400 million of the world’s population [1]
To alleviate the stress placed on endoplasmic reticulum (ER), these proteins must be refolded or degraded by activating a specific cellular response known as ER stress response or unfolded protein response (UPR) [7]
Patients with persistent infection, including 89 chronic hepatitis B virus (HBV) carriers (CHC) which based on sustained normalization of the serum alanine aminotransferase (ALT) levels together with seropositivity for HBeAg and high HBV-DNA levels throughout the study; 101 inactive hepatitis B surface antigen carrier (IHC) which has not shown significant, ongoing necroinflammatory disease; 108 chronic hepatitis B (CHB) which based on clinical symptoms, elevated serum aminotransferase levels, and/or abnormalities of other liver functions; and 198 liver cirrhosis (LC) which showed serum HBsAg, abnormal liver function profiles and portal hypertension, according to the guidelines of the American Association for the Study of Liver Diseases [21] and others [22,23]
Summary
Hepatitis B, called serum hepatitis, is a global health problem that affects more than 400 million of the world’s population [1]. It is estimated that the prevalence of chronic hepatitis B virus (HBV) infection in China is approximately 10– 20% of the population, where it represents the leading cause of cirrhosis and hepatocellular carcinoma [2]. It binds to unfolded proteins and regulates the activation of ER stress transducers such as IRE1, PERK, and ATF6 [9] Based on these backgrounds, the transcriptional activation of the GRP78 is used extensively as a biological marker for onset of the UPR, as well as an unique model for deciphering the mechanisms whereby ER stress upregulates nuclear gene expression. HBV invasion and other physiopathologic changes cause large amount of unfolding or false-folding protein accumulation in the endoplasmic reticulum (ER), which in turn induces expression of GRP78 [12]. A large casecontrol study was conducted to further investigate this hypothesis among a Han Chinese population in Southern China
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