Oral Contraceptives Use, ACE Polymorphism On The Risk Of Stroke In Women

Oral contraception remains as one of the effective contraceptive methods mostcommonly used worldwide. At present, it is estimated that the percentage of oralcontraceptives (OC) use of women around the world was8.5%and was the secondused in all of contraception. Although the prevalence rate of OC use in China is only1.5%, compared with other countries, the absolute number of OC user is larger due toenormous general population. Since it was introduced in the1960s, OC has beenimplicated in increasing cardiovascular risk following use. Stroke is one of the mostcommonly side effects of OC.Stroke is the third leading cause of mortality in the world. About88%of strokeis due to cerebral ischemia and the remaining result from intracerebral hemorrhage(ICH). Stroke is a multifactorial disease and has a number of risk factors such asethnicity, family history, genetic predisposition as well as hypertension, diabetesmellitus, hyperlipidemia, smoking, obesity and alcohol consumption.The risk of stroke with oral contraceptive pill (OCP) use has been extensivelyevaluated. Previous epidemiological studies have shown increased risk ofcardiovascular events associated with OCs in women with hypertension, smoking, ormigraine. Accordingly, these conditions are now considered contraindications to theuse of OCs, particularly in women after age35.The results of three separatemeta-analyses summarizing over30years of studies have shown that oral contraceptive users have about a twofold increased risk of stroke over non-users.Overall, current use of combined OCs was associated with a slightly increasedrisk of haemorrhagic stroke; this increased risk was significant in the developingcountries but not in Europe. accords with the results of Thorogood and colleagues’recent large-scale study of haemorrhagic stroke, which reported no significantincrease in risk of fatal subarachnoid or other haemorrhagic strokes in associationwith current use or ever-use of OCs in the UK.Genetic predisposition is also one of the important risk factors of stroke.Vascular complications are associated with a number of candidate genes such asangiotensin converting enzyme (ACE). D allele of ACE has been reported to beassociated with small vessel ischemic stroke, intima media thickness of commoncarotid artery and primary ICH. ACE is the rate limiting enzyme of renin angiotensinsystem and is involved in vascular remodeling and atherosclerosis. ACE is located onchromosome17q and has two polymorphic alleles D and I, depending on insertionand deletion of287bp alu sequence in intron16.In this study, we first use meta-analysis to discuses the relationship betweenACE gene polymorphism and stroke risk, then on this basis, a case-control designedstudy was conducted in Chinese women population, in order to evaluate the effects ofOC use and hereditary susceptibility on the risk of stroke and provide suggestions forguiding safe use of OC and studying etiological factor of women with stroke.Part ⅠStroke is a complex heterogeneous disease caused by multiple genes andenvironmental factors, and with complex etiologies. Established causal risk factorssuch as hypertension and smoking are estimated to account for50%of vasculardisease risk. Therefore the identification of novel markers of stroke risk is of keyimportance, both for risk prediction and potential modification to reduce future events.The angiotensin-converting enzyme (ACE), a key enzyme in the renin-angiotensinsystem, plays an important role in vascular wall homeostasis.2-4Regulation of circulation and probably tissue ACE activity are under strong genetic control. TheACE gene located on chromosome17q23has an insertion/deletion (I/D)polymorphism in the noncoding region of the gene. It has been shown that higherserum ACE activity is present in subjects with the D compared with the I allele.Numerous studies have reported a positive or null relation between the D allele andcerebrovascular diseases, but findings have been controversial.[Objective] In this paper, we reviewed available literatures to determine whether theassociation between ACE I/D gene polymorphism and subtype of stroke (hemorrhagicstroke and ischemic stroke) exists and, if so, the magnitude of the risk.[Methods] Studies based on EMBASE, MEDLINE databases referenced literature upto Dec.2011. Articles published in English describing I/D gene polymorphism andstroke outcomes were retrieved, and relevant data were abstracted.[Results]1. Meta-Analysis of association between ACE I/D polymorphism and stroke risk.The overall summary estimate showed ID/DD genotype was associated withincreased risk of ischemic stroke(OR=1.25;95%CI:1.11-1.42). But the summary riskfor hemorrhagic stroke was not significant(OR=1.10;95%CI:0.70-1.74).2. Subtype analysis of ACE I/D polymorphism and risk of stroke.In subtype analysis, ID/DD genotype increased significantly the risk of hemorrhagicstroke (OR=1.76;95%CI:1.38-2.24) and ischemic stroke (OR=1.37;95%CI:1.12-1.69) in population from Asia and the risk of ischemic stroke (OR=1.13;95%CI:1.00-1.28) in population from Europe and America.[Conclusion] Summary results indicate that risk of hemorrhagic stroke and ischemicstroke is increased in persons has ID/DD genotype based on populations from Asia. Part Ⅱ Association of OC use and ACE polymorphism on the risk of stroke in womenAs it was introduced in the1960s, OC has been implicated in increasingcardiovascular risk following use. Stroke is a complex heterogeneous disease andcaused by multiple genes and environmental factors. The renin-angiotensin system(RAS) is known for its role in the regulation of blood volume, water balance andsystemic vascular resistance. Some recent studies suggested that AngⅡ, onecomponent of RAS, plays an important role in regulating blood flow in the brain. Theaction of AngⅡ on blood vessels spans beyond vasoconstriction and includesenhanced production of reactive oxygen species (ROS), decreased NO production,increased smooth muscle cell proliferation, enhanced prostaglandin release andvascular permeability, and often promotes blood vessel injury. Further, estrogen ofOC can activate RAS, may enhanced production of AngⅡ, and increase the risk ofstroke. Thus, we hypothesized that OC use, ACE gene polymorphism and there jointactions were associated with the risk of stroke in Chinese women.[Objective] To evaluate the associations of OC exposure, ACE geng polymorphismand their joint effects with the risk of stroke in Chinese women.[Methods] Base the reporting system of cardiovascular disease, which wasestablished in Taicang County of Suzhou City and Rudong County of Nantong City inJiangsu Province, a case-control study was conducted. Incident cases of strokeidentified between1July2000and30June2009was enrolled. A total of1372femalesubjects were recruited, of whom453stroke women were enrolled. Then one hospitalcontrol and one healthy community control were matched on region and age (±3years),919controls were recruited. Two polymorphisms of the ACE gene wereselected. The genotyping for two polymorphisms of ACE gene were detected by PCR(I/D) and Tagman (A-240T).[Results]1. Associations between OC use and strokeThe study demonstrated significantly increased stroke risk with OC use (OR=1.31; 95%CI:1.01-1.71), especially for hemorrhagic stroke (OR=1.83;95%CI,1.25-2.66);the risk of hemorrhagic stroke and ischemic stroke gradually increased with thecumulative time of OC use in women (Ptrend<0.0001). Compared with none users, therisk of stroke significantly increased among those with cumulative time of OC≥20years (OR=2.07;95%CI:1.30-3.29).2. Subtype analysis of OC and risk of strokeOC users were associated with a increased stroke risk among younger persons (lessthan55years)(OR=3.13;95%CI:1.74-5.65). OC significantly increased risk ofhemorrhagic stroke in subjects who were hypertension cases (OR=1.80;95%CI:1.18-2.75).3. Associations between ACE gene polymorphisms and strokeWomen with ID/DD genotypes of I/D locus indicated significantly increased risk ofhemorrhagic stroke (OR=2.37;95%CI:1.46-3.84) and ischemic stroke (OR=1.94;95%CI:1.36-2.76). TA/TT genotypes of A-240T locus significantly increased risk ofischemic stroke (OR=1.64;95%CI:1.18-2.26). But TA/TT genotypes of A-240Tlocus had no significant association with hemorrhagic stroke (OR=1.33;95%CI:0.91-1.96).4. The joint effect analysis.Women with ID/DD genotypes of I/D locus ues OC significantly increased the risk ofhemorrhagic stroke (OR=4.59;95%CI:2.21-9.51) and ischemic stroke (OR=2.08;95%CI:1.28-3.39). Women with TA/TT genotypes of A-240T locus use OC alsosignificantly increased the risk of hemorrhagic stroke (OR=2.50;95%CI:1.42-4.38)and ischemic stroke (OR=1.81;95%CI:1.15-2.86).5. Analyses of risk factors for stroke in Chinese womenThe risk factors for stroke included hyperlipidemia, OC use, hypertension, andID/DD genotype. OC use, hypertension, and ID/DD genotype were risk factors forhemorrhagic stroke. While hyperlipidemia, hypertension, and ID/DD genotype wererisk factors for ischemic stroke. Most of the stroke could be attributable to `hypertension.[Conclusion] The risk of stroke significantly increased among women use OC,especially for hemorrhagic stroke. The ACE gene polymorphisms demonstratedsignificant impact on the risk of stroke. And the joint effect between women usingOC and ACE gene polymorphisms significantly increased the risk.