ESR2 Genetic Variants and Combined Oral Contraceptive Use Associated with the Risk of Stroke

Abstract

There is accumulating evidence suggesting an important role of estrogen receptor-β in the development of cardiovascular disease. The present study aims to investigate the relationship of estrogen receptor β gene (ESR2) polymorphisms with stroke risk in Chinese women, and further evaluate the gene-environment interaction of ESR2 and combined oral contraceptive (COC) use on stroke risk. A case-control study was conducted with 446 first-ever stroke patients and 864 control subjects recruited from our prospective female cohort. Four polymorphisms of ESR2 gene were genotyped, and the information of contraceptive use was obtained by a face-to-face interview. Women with rs1256065 CC genotype were at a 1.59 fold increased risk of stroke. Subtype analyses showed that the risk genotype of rs1256065 was associated with ischemic stroke, but not with hemorrhagic stroke. AA genotype of rs4986938 showed a significant correlation with an elevated risk of hemorrhagic stroke. COC users with rs1256065 CC genotype had a 2.36 fold increased risk of stroke, compared with the non-users with the wild-type genotype. Moreover, a significant multiplicative interaction on hemorrhagic stroke was detected between COC use and rs4986938 (pinteraction=0.023). The risk of hemorrhagic stroke was significantly elevated among carriers of rs4986938GA or AA genotype combined with COC use. No associations were observed for rs1256049 and rs1271572. ESR2 genetic polymorphisms were associated with the risk of first-ever stroke in Chinese women, and the AA genotype of rs4986938 combined with COC use could significantly increase the risk of hemorrhagic stroke.