Combined Oral Contraceptive Use, ESR2 Genetic Variants And The Risk Of Stroke In Chinese Women Population

Section 1Current use of oral contraceptives and the risk of first-ever ischemic stroke:a meta-analysis of observational studies[Background] Stroke is one of the rare but serious adverse reactions of oral contraceptive (OC) use. Since the introduction of OCs in the 1960s, the relationship between OC use and ischemic stroke risk has been assessed in many case-control studies and cohort studies, however, the results of these studies were inconsistent. This study aims to evaluate the relationship between OC use and first-ever stroke risk comprehensively through the meta-analysis.[Objectives] To evaluate the risk of first-ever ischemic stroke associated with current use of oral contraceptives, and to describe how the risk was influenced by estrogen dose, progestin type, and study characteristics.[Methods] We obtained relevant articles published between 1970 and March 2014 by conducting a search of Pubmed, Embase and the Cochrane Library. Two investigators independently identified eligible studies based on selection criteria and extracted information. The quality of studies was assessed with the Newcastle-Ottawa scale (NOS). Pooled odds ratios were calculated with a random-effects meta-analysis model, and all analyses were carried out with Stata 12.0.[Results] A total of 18 independent studies (3 cohort studies and 15 case-control studies) were identified. The overall summary odds ratio for first-ever ischemic stroke risk associated with current OC use compared with noncurrent OC use was 2.47 [95% confidence interval (CI),2.04-2.99]. The risk of ischemic stroke among current OC users decreased significantly with decreasing estrogen dose:OCs of ≥50μg ethinyl estradiol (EE),30-40 ug EE,20 ug EE and progestin only pills implied odds ratios of 3.28 (95%CI,2.49-4.32),1.75 (95%CI,1.61-1.89),1.56 (95%CI,1.36-1.79), and 0.99 (95%CI,0.71-1.37), respectively. Combined with<50 ug EE, except the first-generation progenstins, the other three generations of progestin were associated with an elevated risk of ischemic stroke, and the risk of ischemic stroke among users of the fourth-generation progestins was the lowest.[Conclusion] Data from observational studies suggest that current use of modern OCs is associated with an increased risk of first-ever ischemic stroke. OCs containing lower estrogen doses inclined to contribute to a smaller elevated risk of ischemic stroke.Section 2Combined oral contraceptive use, ESR2 genetic variants and the risk of stroke in Chinese women population[Background] Stroke is one of the common diseases threatening human health, and its pathogenesis is extremely complex. Hypertension, smoking, obesity, and combined oral contraceptive (COC) use are all the important risk factors for stroke, and COC use is a risk factor peculiar to women. Moreover, recently several studies have found that estrogen receptor β gene (ESR2) polymorphism might play an important role in the development of cardiovascular diseases.[Objectives] The present study aims to investigate the relationship of ESR2 polymorphisms, COC use and their interaction with stroke risk in Chinese women, so as to provide the scientific evidence for finding the stroke genetic susceptible individuals, instructing COC use safely, and conducting the etiological study and prevention of stroke in women.[Methods] A case-control study was conducted with 446 first-ever stroke patients and 864 age-and region-matched control subjects recruited from our prospective female cohort. Epidemiological information of study objects was collected by conducting questionnaire survey, and venous blood sample was collected from each subject for lipid tests and genotyping assays. Five polymorphisms of ESR2 gene were genotyped by Taqman. The previous research data on ESR1 gene by our group was used for analyzing the interaction between ESR2 and ESR1.[Results] Compared with the non-usrs, COC users had a 1.38-fold increased risk of stroke, and the risk of stroke among COC users increased with the increasing cumulative time of COC use (Ptrend< 0.0001). Women with ESR2 rsl256065 CC genotype were at a 1.59-fold increased risk of stroke (OR,1.59; 95%CI,1.09-2.32). Subtype analyses showed that the risk genotype of rs1256065 was associated with ischemic stroke (OR,1.77; 95% CI,1.14-2.73), but not with hemorrhagic stroke. ESR2 rs4986938 AA genotype showed a significant correlation with an elevated risk of hemorrhagic stroke(OR,3.14; 95% CI,1.37-7.19), while rs4986938 GA genotype seemed to confer a protective effect against ischemic stroke (OR,0.71; 95% CI, 0.51-0.99). COC users with rsl256065 CC genotype had a 2.36-fold increased risk of stroke, compared with the non-users with the wild-type genotype. A significant multiplicative interaction on hemorrhagic stroke was detected between COC use and rs4986938 (Pinteraction= 0.023), and the risk of hemorrhagic stroke was significantly elevated among carriers of rs4986938 GA or AA genotype combined with COC use. Moreover, a gene-gene interaction on hemorrhagic stroke was observed between ESR1 rs2234693 and ESR2 rs4986938 (Pinteraction= 0.029), and compared with women carrying rs2234693 TT genotype and rs4986938 GG genotype, women with rs2234693 TTå'Œ rs4986938 AA had a 7.5-fold increased risk of hemorrhagic stroke (95%CI,2.46-22.89).[Conclusion] COC use and ESR2 polymorphisms were significantly associated with the risk of first-ever stroke and its subtypes in Chinese women. A synergetic interaction (ESR2 rs4986938-COC) and an antagonistic interaction (ESR2 rs4986938-ESR1 rs2234693) were firstly observed on hemohrrhagic stroke.