title: 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.
authors.affiliation: Institute of Infectious Diseases, Southwest Hospital, the Third Military Medical University, Chongqing 400038, P R China.
authors.forename: Zehui
authors.initials: Z
authors.lastname: Yan
authors.forename: Wenting
authors.initials: W
authors.lastname: Tan
authors.forename: Baoyan
authors.initials: B
authors.lastname: Xu
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Dan
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.forename: Chunqing
authors.initials: C
authors.lastname: Deng
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Shun
authors.initials: S
authors.lastname: Tan
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.forename: Guohong
authors.initials: G
authors.lastname: Deng
mesh_terms: D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis / Q000235:genetics* / Q000401:mortality / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D047628:Estrogen Receptor alpha