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

Stroke is a very important disease leads to mortality and morbidity all over the world. A higher prevalence of stroke may exist among women aged 45 to 54 years compared with similarly aged men. And the prevalence of stroke among women will arise after middle age. It just in USA, the financial expenditure for stroke treatment reached up to 58 billion dollars. In China, cerebrovascular diseases was listed to first two kinds of cause of death, high reached 20.36%. Obviously, stroke bring huge financial burden to the family and society. Stroke is becoming a major public health problem in our country.Oral contraceptive (OC) is composed by synthetic estrogen and progestin. Ethinyloestradiol is the most used estrogen. At present, it is estimated that the percentage of OC use of women around the world is 10% and the third used in all of contraception. Although the prevalence rate of OC use in China is only 1.2%, compared with other countries, the absolute number of OC user is larger due to enormous general population. The safety of OC has become in the spotlight since their introduction in 1960s. Many studies have suggested that OC use is associated with increased risk of cerebrovascular diseases; stroke is one of the serious adverse reactions of OC use. The association between high-estrogen OC and stroke is well established. In order to eliminate the serious adverse reactions caused by OC, lots of measures were adopted, including lower doses of estrogen and improve formula for decades. However, many studies investigated the relationship between low dose OC and stroke still found the risk was evaluated.Stroke is a complex heterogeneous disease and caused by multiple genes and environmental factors. The renin-angiotensin system (RAS) is known for its role in the regulation of blood volume, water balance and systemic vascular resistance. Some recent studies suggested that AngⅡ, one component of RAS, plays an important role in regulating blood flow in the brain. The action of AngⅡon blood vessels spans beyond vasoconstriction and includes enhanced production of reactive oxygen species (ROS), decreased NO production, increased smooth muscle cell proliferation, enhanced prostaglandin release and vascular permeability, and often promotes blood vessel injury. Further, estrogen of OC can activate RAS, may enhanced production of AngⅡ, and increase the risk of stroke.In this study, we first use meta-analysis to discuses the relationship between OC use and hemorrhagic stroke risk, then on this basis, a case-control designed study was conducted in Chinese women population, in order to evaluate the effects of OC use and hereditary susceptibility on the risk of stroke and provide suggestions for guiding safe use of OC and studying etiological factor of women with stroke.PartⅠOral Contraceptives and the Risk of Hemorrhagic Stroke: A Meta-AnalysisStroke is one of the rare but serious adverse reactions of oral contraceptives use. The association between OC use and ischemic stroke was evaluated in many case-control and cohort studies during the 1960s and 1970s. But studies about the relationship between OC use and haemorrhagic stroke are limited. Most studies of haemorrhagic stroke have focused on subarachnoid haemorrhage, but these data are controversial. Epidemiological studies found that the incidence, types and mortality of stroke show difference in different regions. In most western countries, ischemic type is the most common stroke, about 70%-80% of the total stroke patients are ischemic type; but in China, the incidence of haemorrhagic stroke is obviously higher than western countries. The findings of previous studies of the effect of OC use on risks of haemorrhagic stroke are limited because of the small numbers of participants and inadequate differentiation of stroke type. So, we performed a meta-analysis of published studies to explore the association of OC use and the risk of hemorrhagic stroke, and to analyze potential reasons for discrepant results.[Background] In this paper, we review available literatures to determine whether the association between oral contraceptives use and hemorrhagic stroke exists and, if so, the magnitude of the risk.[Study design] Studies based on EMBASE, MEDLINE and Cochrane Library databases referenced literature since oral contraceptives marketed was carried out. Articles published in English describing oral contraceptives use and hemorrhagic stroke outcomes were retrieved, and relevant data were abstracted.[Results] 15 studies were included in overall meta-analysis. The overall summary estimate showed current oral contraceptives use was associated with increased risk of hemorrhagic stroke (RR, 1.42; 95% CI, 1.12-1.79, P=0.004). But the summary risk from cohort studies demonstrated no significantly increased stroke risk with oral contraceptives use (RR, 1.82; 95% CI, 0.77-4.32, P=0.17); in contrast, risk estimate from case-control studies showed a significant association (RR, 1.43; 95% CI, 1.23-1.66; P=0.004). High estrogen dose oral contraceptives (RR, 1.67; 95% CI, 1.34-2.08) appeared to impart a greater risk than low dose (RR, 1.41; 95% CI, 1.03-1.93), but the difference was not significant (P=0.182). The RR of hemorrhagic stroke due to oral contraceptives use was significant greater in women who smoked.[Conclusions] Summary results indicate that risk of hemorrhagic stroke is increased in current oral contraceptives users, even with low dose preparations, but association is weak.PartⅡAssociation of OC use and AGT polymorphism on the risk of stroke in womenStroke is a complex heterogeneous disease caused by multiple genes and environmental factors, and with complex etiologies. It is as known, hypertension is the most important traditional risk factors for stroke. Besides, dyslipidemia, gender, smoking, drinking and diabetes mellitus are also play important roles. Recently, a number of recent case-control studies and meta-analysis demonstrated strong contribution of inherited factors in influencing stroke susceptibility.The rennin-angiotensin system, an endocrine system responsible for systemic blood pressure regulation, salt and water homeostasis and for maintaining vascular tone, which act directly in impacting cardiovascular disease development. Polymorphisms in many components of RAS were shown to cooperate in modifying angiotensin II (AngⅡ) effects, including vasoconstriction and extracellular collagen matrix synthesis, and were linked with stroke development. Many studies reported that, estrogen, the mainly component of OC, could significantly increase the serum AGT level of RAS. That suggeste OC use may impact the stroke risk of women. Thus, we hypothesize that OC use, AGT gene polymorphism and there joint effect are associated with the risk of stroke in Chinese women.[Objective] To evaluate the associations of OC exposure, AGT gene polymorphism and their joint effects with the risk of stroke in Chinese women.[Methods] Base the reporting system of cardiovascular disease, which was established in Taicang County of Suzhou City and Rudong County of Nantong City in Jiangsu Province, a case-control study was conducted. Incident cases of stroke identified between 1 July 2000 and 30 June 2009 was enrolled. A total of 1372 female subjects were recruited, of whom 453 stroke women were enrolled. Then one hospital control and one healthy community control were matched on region and age (±3 years), 919 controls were recruited. Three polymorphisms of the AGT gene (A-20C (rs5050) and A-6G (rs5051) in the 5'-untranslated region and C11535A (rs7079) in the 3'-untranslated region) were selected. The genotyping for three polymorphisms of AGT gene were detected by Taqman.[Results]1. Associations between OC use and strokeThe study demonstrated significantly increased stroke risk with OC use (OR, 1.33; 95%CI: 1.06-1.67), especially for hemorrhagic stroke (OR, 1.66; 95%CI, 1.19-2.33); the risk of hemorrhagic stroke and ischemic stroke gradually increased with the cumulative time of OC use in women (P<0.0001, P=0.0029). Compared with none users, the risk of stroke significantly increased among those with cumulative time of COC use15~20 and≥20 years (OR, 1.70; 95%CI: 1.16-2.50; OR, 2.09; 95%CI: 1.42-3.09).2. Associations between AGT gene polymorphisms and strokeWomen with AG/GG genotypes of A-6G locus, or CA/AA genotypes of C11535A locus indicated significantly reduced risk of ischemic stroke (OR, 0.65; 95%CI, 0.48-0.88; OR, 0.62, 95%CI, 0.45-0.85). But the three locus on AGT gene had no significant association with hemorrhagic stroke.3. The joint effect analysisWomen use OC with AA genotype of A-20C locus or AG /GG genotype of A-6G locus or CA/AA genotype of C11535A locus had increased risk for hemorrhagic stroke (OR, 1.99; 95%CI, 1.34-2.97; OR, 1.84; 95%CI, 1.15-2.94; OR, 1.73; 95%CI, 1.06-2.85). But women use OC with AC/CC genotype of A-20C locus significantly increased the risk of ischemic stroke (OR, 1.50; 95%CI, 1.01-2.24). [Conclusion] The risk of stroke significantly increased among women use OC, especially for hemorrhagic stroke. The AGT gene polymorphisms demonstrated significant impact on the risk of ischemic stroke. And the joint effect between women using OC and AGT gene polymorphisms significantly increased the risk.