Study On The Relationship And Mediation Effect Between Combined Oral Contraceptive Use,ESR1 Genetic Variants And The Risk Of Stroke

Stroke is a complex disease affected by environmental and genetic factors,with high incidence,high mortality and high disability rate,which seriously affects human health and brings serious economic burden to social families.Risk factors such as hypertension,diabetes,smoking and alcohol consumption have been identified,while women also have specific risk factors such as COC exposure and pregnancy.Combined oral contraceptives are one of the most commonly used contraceptive methods in women,which is widely accepted because of its high efficiency,convenience and reversibility.Since their introduction in the 1960 s,researchers have found that oral contraceptives also have a series of side effects,such as irregular bleeding,nausea,headache,weight gain and venous thromboembolism.Stroke is a serious side effect of COC use,which has been concerned by researchers.Recent studies on the association between COC use and stroke risk are not always consistent,which may be due to the differences in doses of COC and in the study population.The mechanism of the effect of COC exposure on stroke risk is not clear.Observational studies have found that COC exposure was related to lipid metabolism,and oral contraceptives could significantly increase the level of blood lipid.In addition,hyperlipidemia has been identified as an important risk factor for stroke.Therefore,COC exposure may affect the risk of stroke by affecting lipid metabolism.COC is composed of estrogen and progestin.The biological function of estrogen is mainly mediated by estrogen receptor α(ERα)and estrogen receptor β(ERβ),which are encoded by estrogen receptor α gene(ESR1)and estrogen receptor β gene(ESR2),respectively.ESR gene mutation may lead to abnormal expression and function of estrogen receptor protein,and affect the biological effect of estrogen,thus affecting the pathogenesis of cardiovascular and cerebrovascular diseases.Several studies have found that ESR1 gene rs2234693 is associated with the risk of stroke,but there is no study on the association between ESR1 gene polymorphism and stroke in Chinese women.Objective: To investigate the relationship between COC exposure,ESR1 gene mutation and stroke risk,and to explore the role of lipid metabolism in the association of COC exposure and stroke risk,for the sake of scientific guidance on the safe use of COC and scientific basis on the etiological research and prevention on stroke in women.Methods: In the first part,a meta-analysis was used to evaluate the association between COC exposure and the risk of hemorrhagic stroke.In the second part,a case-control design was conducted based on the prospective female cohort of contraceptives in China.Five polymorphisms of ESR1 gene(rs2234693,rs4870056,rs1709183,rs6902771 and rs2431260)were genotyped by Taqman and the association between these SNPs and stroke risk was detected.The interaction between COC exposure and ESR1 gene was also studied.In the third part,the mediation effect of lipid metabolism on the relationship between COC exposure and stroke risk was analyzed by VanderWeele mediation analysis.Results:(1)Current OC use was significantly correlated with hemorrhagic stroke risk(OR=1.39;95%CI: 1.05-1.83).In addition,the risk of hemorrhagic stroke was further increased in OC users with additional risk factors including current smoking,hypertension,and history of migraine.(2)ESR1 rs4870056 AA genotypes and rs6902771 TT genotypes significantly decreased the risk of hemorrhagic stroke(rs4870056 AA versus GG/GA,adjusted odds ratio(OR): 0.42,95% confidence interval(CI): 0.21-0.83;rs6902771 TT versus CC/CT,adjusted OR: 0.52,95%CI: 0.29-0.973).Moreover,COC users carrying rs4870056 GG/GA genotypes or rs6902771 CC/CT genotypes had a remarkably elevated risk of hemorrhagic stroke(OR=4.05,95%CI:1.57-10.43;OR=2.88,95%CI:1.33-6.24).(3)ApoB played an important role in the association between COC exposure and stroke risk(ORIE=1.073,95% CI: 1.010-1.149,Proportion mediated(PM): 23.89%),especially in the risk of ischemic stroke(ORIE=1.093,95% CI: 1.016-1.193,PM=45.56%).Conclusion: Current use of OCs could contribute to a moderate increased risk of hemorrhagic stroke.The combination of COC use and ESR1 rs4870056 GG/GA or rs6902771 CC/CT genotype could also increase the risk of hemorrhagic stroke.In addition,ApoB played an important role in the relationship between COC exposure and stroke risk.Therefore,COC users should be monitored on blood lipid levels regularly to prevent stroke.Other birth control methods should be considered for women carrying rs4870056 GG/GA or rs6902771CC/CT genotypes of the ESR1 gene and for women with higher lipid levels.