It not only binds to unfolded proteins but also regulates the activation of ER stress transducers such as IRE1, PERK, and ATF6. Based on these backgrounds, the transcriptional activation of the GRP78 is used extensively as a biological marker for onset of the UPR. With respect to liver disease, GRP78 may play an important role in HBV morphogenesis by regulating proper folding of the L protein and/or assembly of the envelope proteins. GRP78 has also been identified as a transformation-associated gene in hepatocellular carcinoma. HBV invasion and other physiopathologic changes cause large amount of unfolding or false-folding protein accumulation in the endoplasmic reticulum, which in turn induces expression of GRP78. Host genetic factors are widely viewed as the common basis of the different outcomes of HBV infection. Our current study demonstrated a statistical relationship of rs430397 polymorphism of GRP78 gene with HBV-related LC. Compared with individuals with non-HBV-infection or self-limited-infection, patients with LC were significantly more likely to carry allele A. For the genotype, the proportion of the AA genotype in patients with LC was (+)-JQ1 clinical trial higher than that in non-HBV-infected individuals. This finding indicated that patients carry allele A or genotype AA have an increased risk of LC compared with those carry allele G or genotype GG. In addition, logistic regression analysis showed that rs430397 genotype had an increased susceptibility to LC with a dose-dependent manner. The functional severity of LC is usually described by CPS. According to CPS, patients of LC in the present study were classified into calss A, class B and class C. Notably, allele A and genotype AA constitute risk factors for the progression of advanced LC. It may suggest that rs430397 may also be a determinant for the degree of LC severity. Although the genotype distribution of rs430397 was not significantly different between patients with and without HBeAg, when taking immune response phases of infection into account, the frequencies of allele A and heterozygote AG were significantly higher in phase IV group compared with phase I group and phase III group. This result does not reject the effect of rs430397 G.A on HBeAg maturation or seroconversion. Rather, HBV infected patients with allele A and heterozygote AG have a higher risk of developing HBeAg-negative CHB and LC. It was verified subsequently as we demonstrated a statistical relationship of the rs430397 at allele and heterozygote level with the progress of HBV infection. Clinically, HBV infection does not invariably result in chronic hepatitis since the host possesses the ability to eliminate the virus spontaneously in most cases. In acute infection, there is a persistence of HBsAg, HBeAg, and HBV-DNA. After the acute hepatitis resolves, serum transaminases levels usually fall but may remain abnormal.