Sex-specific association of estrogen receptor 2 polymorphisms with hepatitis C virus infection outcomes in a high-risk Chinese Han population

Hepatitis C virus (HCV) has different clinical and biological characteristics in women versus men, which suggests the potential involvement of estrogen. Estrogen signaling is mediated by the estrogen receptor, and genetic variations in the estrogen receptor gene might affect the pathology of HCV infection. We performed logistic regression analysis to explore the associations between rs1256049, rs4986938 and rs944459 polymorphisms of the estrogen receptor 2 gene (ESR2) and HCV infection outcomes. The variant A allele of rs4986938 was associated with an increased HCV infection susceptibility in the males (additive model: adjusted OR=1.493, P=0.010) and a significantly reduced risk of HCV infection in the female subgroup (GA vs. GG: adjusted OR=0.710, P=0.012; dominant model: adjusted OR=0.686, P=0.004; additive model: adjusted OR=0.703, P=0.002). In addition, females carrying the rs4986938 AA genotype appeared to clear HCV spontaneously more readily (adjusted OR=0.237, P=0.011), and additive model analyses showed that each additional allele contributed a decreased risk of approximately 34% for HCV chronicity (adjusted OR=0.659, P=0.006). Furthermore, a significant multiplicative interaction between the combined rs1256049 and rs4986938 genotypes was found to decrease HCV infection risk (adjusted OR=0.583, P=3.000×10−4). The area under the curve, based on the model and including age, gender, HCV genotypes and the three SNPs, was significantly related to the clearance of HCV (P=0.003). We provide here the first report that rs4986938 in the ESR2 gene played a potential sex-specific role in the etiology of HCV infection in a high-risk Chinese Han population, suggesting that ESR2 is a candidate susceptibility gene for HCV infection and viral clearance.