A cis-acting regulatory variation of the estrogen receptor α (ESR1) gene is associated with hepatitis B virus-related liver cirrhosis

Abstract

The hepatic fibrogenesis and sexual dimorphism of hepatitis B virus-related liver cirrhosis (HBV-LC) are related to estrogen and its receptors. Abnormal expression of estrogen receptor α (ESR1) is implicated in the development of cirrhosis in both animal models and humans. Here, we examine whether the ESR1 polymorphisms are related to HBV-LC risk among chronic HBV carriers, and we investigate the functional significance of positively associated polymorphisms. A total of 2,404 unrelated Chinese HBV carriers were recruited to conduct the two-stage designed case-control study. Two ESR1 haplotype tagging polymorphisms, c.30T>C (rs2077647) and c.453-397T>C (rs2234693), were genotyped in 1,285 patients with HBV-LC and in 1,119 asymptomatic HBV carriers. We observed a significantly increased susceptibility to HBV-LC associated with the c.30C allele (P = 4.2 × 10(-8) ), c.453-397C allele (P = 2.0 × 10(-8) ), and [c.30C; c.453-397C] haplotype (Dominant model, P = 8.85 × 10(-10) , odds ratio = 1.50, 95% CI 1.32∼1.71) compared with the T alleles and (c.30T; c.453-397T) haplotype of c.30T>C and c.453-397T>C polymorphisms, respectively. Functional analyses were conducted to verify the biological functions of the associated genetic variations and showed that the c.453-397T>C polymorphism is a novel c.453-397C allele-specific and c-myb-dependent enhancer-like cis-acting regulatory variation and could be part of the genetic variations underlying the susceptibility of individuals to HBV-LC.

Limited Effects of Bile Acids and Small Heterodimer Partner on Hepatitis B Virus Biosynthesis In Vivo

“…Mice were fed a control or a 1% (wt/wt) cholic acid (CA) diet for 7 days. liver (13,28), may preferentially modulate HBV transcription and replication in males, possibly contributing to the greater disease burden associated with chronic HBV infection in men than in women (21,27,60).…”

“…1) (13, 28). The reasons for these differences are currently unclear, but it is worth noting that disease progression is generally more severe in males than in females, indicating that there are sexually dimorphic differences present in both mice and humans (21,27,60).…”

Pregnancy serum facilitates hepatitis E virus replication in vitro

“…ER-a mediated oestrogen plays a major biological function in the liver. Clinical and animal-based experiments have demonstrated that abnormal ER-a expression is closely related to hepatocyte proliferation and liver cirrhosis (Shimizu, 2003;Yan et al, 2011). For instance, HBV X protein can inhibit ER transcription.…”

Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure

“…Additional 334 HBV carriers with severe CHB (S-CHB) flare were also enrolled and used as controls for the reactivation of hepatitis B. Five hundred and ten patients with LC with acute or chronic decompensation but without ACLF were used as LC controls, who were from our previous study 17. All participants were positive for HBV surface antigen at least 12 months, and had no serological evidence for coinfection or superinfection with HCV, hepatitis D virus and HIV.…”