Estrogen Receptor α Polymorphisms Associated With Susceptibility to Hepatocellular Carcinoma in Hepatitis B Virus Carriers

Background & Aims: Overexpression of estrogen receptors (ESRs) is implicated in the development of hepatocellular carcinoma (HCC) in both animal models and humans. We examined whether the ESR1 polymorphisms were related to HCC risk among chronic hepatitis B virus carriers. Methods: Six ESR1 polymorphisms, which are (TA)_n repeat in the promoter, T29C at codon 10 in exon 1, PvuII and XbaI site in intron 1, C136474G at codon 325 in exon 4, and A252966G in intron 5, were genotyped in 248 patients with HCC and 239 controls. The associations with the susceptibility to HCC were estimated by logistic regression. Allele-specific transcription difference of ESR1 messenger RNA was performed by real-time quantitative polymerase chain reaction. Results: We observed a statistically significant increased susceptibility to HCC associated with the homozygous alleles with a high number of TA repeats (assigned as H/H genotype; odds ratio [OR], 2.66; 95% confidence interval [CI], 1.44–4.94; P = .0018), T29C C/C genotype (OR, 2.31; 95% CI, 1.25–4.26; P = .0076), and PvuII C/C genotype (OR, 2.19; 95% CI, 1.27–3.78; P = .0048) compared with the homozygous alleles with a low number of TA repeats (assigned as L/L genotype), T29C T/T, and PvuII T/T genotype, respectively. In accordance, the relative messenger RNA levels of the at-risk C allele of T29C were consistently higher than those of the T allele in heterozygous cells. Conclusions: Our findings suggest that the genetic polymorphism in ESR1 may play a role in mediating susceptibility to HCC in Chinese hepatitis B virus carriers.

Abbreviations used in this paper: CI, confidence interval, ESR, estrogen receptor, LD, linkage disequilibrium, OR, odds ratio, PCR, polymerase chain reaction, RFLP, restriction fragment length polymorphism