| Stroke,known as cerebrovascular accident,is believed to be a kind of complex diseases arising from multiple environment and genetic factors,leads to high morbidity and high mortality all over the world.According to the WHO report,stroke is the second leading cause of death all over the world,is the third leading cause of death in most developing countries,and is the leading cause of disability in America.In China,the percentage of population’s causes of death result from cerebrovascular diseases is about to 25%,about 1 million died of stroke and 75%of patients have different degree of sequelae.Obviously,stroke brings huge financial burden to the family and society.We need to understand the risk factors and pathogenesis of stroke,in order to carry on the effective prevention.However,the pathogenesis and the mechanisms underlying stroke are not fully enunciate.In recent years,studies have shown that combined oral contraceptives（COC）,estrogen metabolism and signaling pathway gene polymorphism is another important cause of cadio-cerebrovascular diseases.COC come into the market which are combined of estrogen and progesterone in the developed countries in the early 1960s.COC use remains as one of the effective,safe,convenient and non-contraceptive benefit contraceptive methods most commonly used worldwide.But its safety has been controversial.Stroke is a rare and serious side effect of COC use,which has caught a great number of researchs,attention.The results of the studies about the connection between COC use and stroke carried out among different populations are not consistent.These studies suggest that genetic factor plays an important role in the susceptibility of stroke.Estrogen is a kind of steroid hormones,including estradiol,estrone,and estrio.Estrogen plays important effects on the reproductive system,and regulates blood lipid metabolism,improves endothelial function,prevents the atherosclerosis.Therefore the main biological effects of estrogen are influenced not only by the expression of estrogen,but also by the variant of estrogen receptor（ESR）.It has been reported that,ESR1 polymorphisms were associated with stroke among Indian women.ESR1polymorphisms may affect the expression of ESR1 and investigate the development of stroke.The PvuII（rs2234693）and XbaI（rs9340799）were the most dicussed locis in ESR1 gene.Basic research suggests that ESR1 polymorphism influences the ESR active transcription and expression.To provide the interpretation of the molecular level for ESR1 gene polymorphism in the occurrence of stroke.In this study,we used different bioinformatics methods to screen SNPs in ESR1,and analyzed the association between these SNPs and the susceptibility of stroke.We found the ESR1 polymorphisms were associated with stroke risk.Furthermore,the joint effects of gene-gene,gene-environment were also discussed.The results from this study will be helpful in preventing stroke,instructing contraceptive use,and promoting the health of women.[Objectives]To evaluate the associations of COC exposure,ESR1 gen polymorphism and their joint effects with the risk of stroke in Chinese women.[Methods]A case-control study was conducted based on the female cohort of contraceptives in China.453 first-ever female stroke cases and 919 age-and region-matched controls were recruited from the cohort.Each participant was scheduled for a face-to face interview by using a standard questionnaire to collect information on demographic data,contraceptive use history,family history,reproductive history and so on.After interview,approximately 6 ml of venous blood sample was collected from each participant for lipid tests and genotyping assays.Six single nucleotide polymorphisms（SNPs）（rs2234693,rs9340799,rs2077647,rs2228480,rs3798758,rs2813544）of the ESR1 gene were selected.The genotyping of ESR1 gene were detected by Tagman.And we analyzed the associations of ESR1gene polymorphisms with the risk of stroke.[Results]1.Associations between COC use and strokeThe study demonstrated significantly increased stroke risk with COC use（adjusted OR=1.31,95%CI:1.01-1.71）,especially for hemorrhagic stroke（adjusted OR=1.83,95%CI:1.25-2.66）.The risk of hemorrhagic stroke and ischemic stroke gradually increased with the cumulative time of COC use in women(Ptrend<0.0001).Compared with none users,the risk of stroke significantly increased among those with cumulative time of COC≥20 years（adjusted OR=2.07,95%CI:1.30-3.29）.2.Stratification analysis of COC and risk of strokeAfter adjustment for age,area,BMI,hypertension,hyperlipidemia,the results showed that COC users were associated with an increased stroke risk among younger persons（less than 55 years）（adjusted OR=2.95,95%CI:1.62-4.13）.Similarly,the COC users had a 2.13-fold（adjusted OR=3.13,95%CI:1.74-5.65）increased risk of hemorrhagic stroke compared with the non-users.Moreover,COC users were associated with an increased ischemic stroke risk（adjusted OR=2.26,95%CI:1.23-4.16）.COC significantly increased risk of hemorrhagic stroke in subjects who were hypertension cases（adjusted OR=1.80,95%CI:1.18-2.75）.3.Associations of ESR1 gene polymorphisms with the risk of ischemic strokeThe genotype distributions of the six SNPs of ESR1 gene have no significance in cases and controls（all P>0.05）.To further test the modifying effects of SNPs on risk of stroke with different stroke subtypes,we performed subtype analyses by hemorrhagic stroke and ischemic stroke.After adjusted the cardiovascular risk factors,the results showed that the variant of rs2234693 of ESR1 gene was positively associated with the risk of ischemic stroke（adjusted OR=0.65,95%CI=0.46-0.91）.It indicated that TC and TC/CC genotypes can decrease the risk of ischemic stroke.However,none of statistically significant associations was observed between five other SNPs（rs9340799,rs2077647,rs2228480,rs3798758 and rs2813544）and risk of ischemic stroke.4.Associations of ESR1 gene polymorphisms with the risk of hemorrhagic strokeWhile the variant of rs2813544 of ESR1 gene was significantly associated with risk of hemorrhagic stroke（AG vs AA:adjusted OR=1.55,95%CI=1.02-2.36;GG vs AA:adjusted OR=3.88,95%CI:1.20-12.55;AG/GG vs AA:adjusted OR=1.66,95%CI:1.11-2.50）.But none of statistically significant associations was observed between five other SNPs（rs2234693,rs9340799,rs2077647,rs2228480 and rs3798758）and risk of hemorrhagic stroke.5.Stratified analyses of SNPs in ESR1 gene by age,BMI,hypertension,hyperlipidemiaThe stratified analyses demonstrated that the risk of ischemic stroke associated with rs2234693 TC/CC genotype was significantly decreased among women aged<55years（adjusted OR=0.48,95%CI=0.26-0.91）,and the association between hemorrhagic stroke risk and rs2234693 TC/CC genotype was also significant among women with aged<55 years（adjusted OR=0.52,95%CI=0.29-0.93）.rs2813544 AG/GG genotypes increased significantly the risk of hemorrhagic stroke among the women with COC use,hypertension,hyperlipidemia.（adjusted OR=2.53,95%CI=1.38-4.67;adjusted OR=1.91,95%CI=1.21-3.03;adjusted OR=2.17,95%CI=1.24-3.79）.6.Haplotype analysis on ESR1 variationsWe performed haplotype analysis on ESR1 variations.There were no haplotypes which may increase or decrease risk of stroke compared with the most common haplotype TAA,even after adjusting for age,area,BMI,hypertension,hyperlipidemia（all P>0.05）.7.Joint effects between COC use and genetic variants with stroke riskCompared with the non-users with wild-type genotypes,COC users with rs2234693TC/CC genotype had a decreased risk of ischemic stroke（adjusted OR=0.52,95%CI:0.33-0.82）after adjustment for covariates.Moreover,COC users with rs2813544AG/GG genotype had an increased risk of hemorrhagic stroke（adjusted OR=1.77,95%CI:0.33-0.82）after adjustment for covariates.[Conclusion]The risk of stroke significantly increased among Chinese women who use COC,especially for hemorrhagic stroke.The ESR1 gene polymorphisms demonstrated significant impact on the risk of stroke.And the joint effect between women using COC and ESR1 gene polymorphisms was significantly associated with the risk of stroke. |
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