口服避孕药及遗传变异与中国女性脑卒中发病风险的病例—对照研究
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摘要
口服避孕药的问世是人类节育技术的一次革命。复方口服避孕药（combinedoral contraceptives，COC）指由雌激素和孕激素配伍组成的避孕药。临床实践证明，COC是短效避孕措施中最高效、安全，也是最能有效减少非意愿妊娠的方法之一。但COC于20世纪60年代初在发达国家上市不久就出现COC升高脑卒中、心肌梗塞和静脉血栓栓塞等心脑血管疾病发病风险的报道。尽管近年来随着COC中雌激素含量的降低和孕激素配方的改变而使得COC使用者罹患心脑血管疾病的风险有所下降，但是研究发现该风险在COC使用者中依然显著升高。
在COC相关的健康风险中，脑卒中一直受到研究者的关注。中国是脑卒中高发国家，随着人口老龄化的加速和生活方式的改变，由脑卒中带来的健康和社会问题将愈加凸显。中国人群在脑卒中的发病率、表型、特征和风险因素等方面和欧美人群有着明显的不同，因此了解中国妇女服用COC等与脑卒中的关联及其特征将有助于更好地在中国女性人群中预防脑卒中的发生。
脑卒中是由环境因素和遗传因素共同作用所产生的复杂性疾病。环境因素仅能解释部分脑卒中事件的发生，比如同样服用COC的妇女仅有一小部分发生脑卒中，因此不同的个体对于脑卒中存在遗传易感性的差异。近年来，分析全基因组范围内遗传变异与疾病之间关联的全基因组关联研究（genome-wideassociation studies，GWAS）成为复杂疾病遗传机制研究的重要策略。随着GWAS的开展，越来越多的新的与脑卒中易感性相关联的单核苷酸多态性（singlenucleotide polymorphism，SNP）位点被报道。但是现有的脑卒中GWAS多在欧美人群中进行，中国人群与欧美人群相比等位基因频率存在着差异，那么在中国人群中能否重现这样的关联是一个值得探究的问题。
此外，风险因素之间的交互作用在复杂疾病的发生中亦发挥着重要的作用。研究发现，有偏头痛的妇女，如果同时使用口服避孕药或有高血压史或吸烟，将显著增加与之相关的梗塞型脑卒中的发病风险；服用COC联合凝血系统或肾素-血管紧张素系统基因多态会显著增加脑卒中的风险。因此探讨基因-基因和基因-环境因素之间的交互作用对于进一步阐明脑卒中的发病机制具有重要意义。
本研究是建立在国家科技攻关课题“避孕药长期应用安全性研究”前瞻性研究基础上的病例-对照研究，采用传统流行病学和分子流行病学相结合的研究手段，探讨与中国女性脑卒中相关联的风险因素，包括调查COC使用等环境因素和验证GWAS报道的易感SNPs，并探讨环境因素之间、遗传因素之间及环境-遗传因素之间的交互作用，为指导安全避孕提供科学依据，为防治脑卒中、促进女性健康提供有力保障。
第一部分口服避孕药与中国女性脑卒中发病风险的关联研究
口服避孕药是世界范围内广泛使用并且有效的避孕措施之一，目前全球范围内8.8%的育龄妇女口服避孕药进行避孕。虽然中国服用COC妇女的相对人数低于欧美国家，但是由于我国育龄妇女人数众多，故其绝对人数庞大，国产COC自20世纪70年代推广应用以来，曾经使用人数累计达数千万之多。为保证广大育龄妇女的健康，我国在降低COC中雌激素剂量和更新换代方面做了大量研究工作，但是缺乏国产低剂量COC与脑卒中等心脑血管疾病风险的远期安全性研究。
[目的]探讨COC使用等环境因素与中国妇女脑卒中发病风险之间的关联，探讨环境因素之间的交互作用对脑卒中发病风险的影响。
[方法]在对女性避孕药具使用人群随访的基础上前瞻性收集确诊的脑卒中新发病例，并按年龄和地区匹配健康对照和医院对照各一名。对服用COC等风险因素进行流行病学调查，测量血压、身高、体重，并采集空腹静脉血进行脂代谢测定。
[结果]
1. COC使用与中国女性脑卒中发病风险的关联服药妇女发生脑卒中的风险是未服药者的1.56倍。与未服药者相比，COC当前使用者发生脑卒中的风险增加3.05倍，而过去服用COC仅轻度增加脑卒中的发病风险。脑卒中的发病风险随着累计服药时间的延长而增加。此外，服用COC显著增加出血型脑卒中的发病风险，其年龄调整OR值为2.23（95%CI1.43-3.48），但与梗塞型脑卒中之间无统计学关联。
2中国女性脑卒中影响因素的多因素分析脑卒中家族史、服用COC、高血压、高血脂、糖尿病是脑卒中发生的风险因素；出血型脑卒中的风险因素为脑卒中家族史、服用COC、高血压、糖尿病；而梗塞型脑卒中的风险因素为年龄、脑卒中家族史、高血压、高血脂、糖尿病；人群中绝大部分脑卒中归因于高血压的发生。
3.风险因素之间的交互作用对脑卒中发病的影响高血压联合脑卒中家族史使脑卒中的发病风险增加21倍；高血压联合高血脂使梗塞型脑卒中的发病风险增加35倍；COC使用联合高血压使出血型脑卒中的发病风险增加18倍，均表现为相加的交互作用。[结论]服用COC是中国女性脑卒中的风险因素，且高血压与COC使用、高血脂、脑卒中家族史等风险因素之间的交互作用显著增加脑卒中的发病风险。
第二部分基于GWAS的遗传变异与中国女性脑卒中发病风险的关联研究
高血压等传统风险因素仅能解释部分脑卒中事件的发生，不同个体之间存在着遗传易感性的差异。近年来日益兴起的GWAS研究提示一些新的易感SNPs与脑卒中的发生之间有着密切的关联。但是目前已有的脑卒中GWAS研究多在欧美人群中进行，中国人群与欧美人群相比，无论在脑卒中亚型特征还是遗传特质方面均有着较大差异，比如，中国人群中出血型脑卒中所占比例较欧美人群高，等位基因的频率分布也与欧美人群有着较大差异。在中国人群中能否重现脑卒中GWAS研究已报道的阳性关联是一个值得探究的问题。
[目的]探讨脑卒中GWAS报道的遗传变异与中国女性脑卒中发病风险之间的关联，并探讨可能的基因-基因和基因-环境因素（COC使用）的交互作用。
[方法]采集脑卒中新发病例和对照的血标本，蛋白酶K消化后采用酚-氯仿法提取基因组DNA，采用PCR TaqMan探针技术对所选位点进行检测分型。对于检测到的阳性位点通过另一独立样本进行验证。
[结果]
1.基于GWAS的遗传变异与中国女性脑卒中发病风险的关联SNPs位点rs9943582、rs10958409、rs1333040、rs10986769遗传变异与脑卒中的发病风险相关联。rs10958409和rs1333040位点的遗传变异主要增加出血型脑卒中的发病风险，在显性模型下，其调整后的OR值分别为1.83（95%CI1.12-3.01）和4.57（95%CI1.38-15.09）。
在验证人群中仅发现rs1333040位点T等位基因携带者发生脑卒中的风险是未携带者的2.41倍。
合并分析结果显示，rs10958409和rs1333040位点遗传变异与中国女性脑卒中及其亚型相关联。
2. SNPs位点之间的联合作用分析：未发现多态位点之间存在联合作用。
3. COC使用联合遗传变异与脑卒中发病风险的关联妇女服用COC联合rs10958409或rs1333040位点遗传变异显著增加脑卒中尤其是出血型脑卒中的发病风险。与不服药且未携带风险等位基因的妇女相比，COC使用联合rs10958409或rs1333040位点遗传变异分别使出血型脑卒中的发病风险增加4.81倍和15.06倍，并且联合作用对脑卒中发病的影响在年龄<50岁的女性中尤为明显。
[结论] SNPs位点rs10958409和rs1333040遗传变异与中国女性脑卒中及其亚型相关联，且该遗传变异联合COC使用显著增加脑卒中尤其是出血型脑卒中的发病风险。
Use of oral contraceptives is considered as an innovative method for contraceptionin human beings. Combined oral contraceptives (COC) are combined estrogen andprogesterone. Clinical practice has demonstrated that COC use is one of the mosteffective and safest short-effect contraception methods for reducing unexpectedpregnancy. However, increased risk of cardio-cerebrovascular diseases such as stroke,myocardial infarction, and venous thromboembolism was reported to be associatedwith COC use since it was on the market in the developed countries in1960s.Although the development of low estrogen doses and altered progestin levels led tofewer cardio-cerebrovascular complications, the increased risk was still documentedin subsequent studies.
More attention has been paid to stroke among all COC related health risks. Theincidence of stroke is much higher in Chinese population. Moreover, with theacceleration of an aging population and changed lifestyle, health and social problemsarising from stroke will be more prominent. Compared with Caucasians, Chinesediffer in incidence rate, phenotypes, clinical characteristics, and risk factors of stroke.Therefore, to explore the associations between COC use and stroke risk will benefitfor stroke prevention in Chinese women.
Stroke is believed to be a kind of complex diseases arising from multiple environmental and genetic factors. Nevertheless, environmental factors could merelyexplain a small part of stroke, for instance, only a few of COC users suffer fromstroke. Therefore, there are differences in genetic susceptibilities in individuals whenthey are exposed to similar environmental factors. Recently, genome-wide associationstudies (GWAS) which analyze the genetic variants covering whole genome havebecome a promising method for the studies of genetic susceptibilities. With theadvances of GWAS, many new single nucleotide polymorphisms (SNPs) werereported to be associated with stroke risk. However, most of these GWAS of strokewere conducted in Caucasians. It is known there is difference of allelic frequencybetween Caucasians and Chinese. Therefore, it is an interesting topic to check theassociations between GWAS SNPs and the risk of stroke in Chinese population.
The interactions between risk factors may have an impact on the development of acomplex disease. Studies showed that in migrainous women, coexistent use of oralcontraceptives or a history of high blood pressure or smoking had greater thanmultiplicative effects on the odds ratios for ischemic stroke associated with migrainealone. In addition, the risk of stroke was significantly elevated in combination ofCOC use with gene polymorphisms of coagulation system and rennin-angiotensinsystem. To explore the possible gene-gene and gene-environment interactions willhelp in elucidating the mechanisms for stroke.
This study was a case-control study based on the prospective cohort which wasestablished with the support of National Key project ‘Study on the long term healtheffects of contraceptives’. Traditional epidemiological and molecular epidemiologicalmethods were applied integratedly in this study. The risk factors for stroke in Chinesewomen, including environmental factors such as COC use, and genetic variantssuggested by GWAS were investigated. Furthermore, the gene-gene andgene-environment interactions were discussed. The results from this study will behelpful in instructing contraceptive use, preventing stroke, and promoting women’shealth.
Part Ⅰ
COC Use and the Risk of Stroke in Chinese Women
COC is a widely used and effective method for contraception. About8.8%women of childbearing age take COC for contraception. Although there are a relativefew women taking COC in China, compared with those in developed countries, thetotal COC users are with a large number due to many women at reproductive age.Moreover, the accumulated number of women who have ever taken domestic-madeCOC since1970s is more than tens of millions. Many studies have been conducted toreduce estrogen doses and change the formulation of COC so as to protect women’shealth, however, there is few study on the long-term health effects related todomestic-made low-dose COC.
[Objective] To illuminate the associations between stroke and environmental factors(COC use) in Chinese women, and explore the possible interactions between theseenvironmental factors.
[Methods] On the basis of a prospective female cohort of contraceptive use, thefirst-ever stroke cases, as well as, two age-and region-matched controls (includingneighbourhoods and hospitalized patients) were recruited. An epidemiologicalinvestigation was conducted to obtain relevant information on possible risk factors,for instance, COC use. Blood pressure, height, and body weight were measured.Peripheral venous blood was taken for lipid tests after an overnight fast.
[Results]
1. The association between COC use and stroke risk in Chinese womenCOC users had a1.56-fold increased risk of stroke, compared with the non-users.Current COC use increased stroke risk by3.05-fold, while past use only slightlyincreased the risk. The stroke risk gradually elevated with the increasing cumulativetime of COC use. Moreover, COC use was significantly associated not with ischemicstroke but with hemorrhagic stroke subtype (OR2.23,95%CI1.43-3.48).
2. Analyses of risk factors for stroke in Chinese women
The risk factors for stroke included family history of stroke, COC use,hypertension, hyperlipidemia, and diabetes mellitus. Family history of stroke, COCuse, hypertension, and diabetes mellitus were risk factors for hemorrhagic stroke.While age, family history of stroke, hypertension, hyperlipidemia, and diabetesmellitus were risk factors for ischemic stroke. Most of the stroke could be attributableto hypertension.
3. Interactions between risk factors on stroke risk
Compared with normotensive women without family history of stroke,hypertensive women with family history of stroke had a22-fold increased risk ofstroke. In combination of hypertension and hyperlipidemia increased the risk ofischemic stroke by35-fold. COC use combined with hypertension elevated the risk ofhemorrhagic stroke by18-fold. Additive interactions between these risk factors weredetected.
[Conclusion] COC use was the risk factor for stroke in Chinese women. Theinteractions between hypertension and other risk factors (COC use, hyperlipidemia,family history of stroke) significantly increased the risk of stroke.
Part ⅡGWAS Suggested Genetic Variants and the Risk of Stroke in Chinese Women
Only a part of stroke could be attributed to the traditional risk factors such ashypertension. Genetic susceptibility does differ in individuals. Recently growing areaof GWAS has suggested several new SNPs associated with stroke risk. Nevertheless,most of these GWAS were conducted in Caucasians. There are differences in strokesubtypes and genetic characteristics when compared Chinese with Caucasians. Thepercentage of hemorrhagic stroke among overall stroke is higher in Chinese,compared with that in Caucasians. Furthermore, there are differences in thedistributions of allelic frequency. It is unknown if these positive associations reportedby GWAS of stroke in Caucasians could be replicated in Chinese.
[Objective] To demonstrate the associations between genetic variants suggested by GWAS and stroke risk in Chinese women, and explore the possible gene-gene andgene-environment (COC use) interactions.
[Methods] Blood samples were taken from first-ever stroke cases and controls.Genomic DNA was extracted by proteinase K digestion and phenol-chloroformextraction. Genotyping of selected GWAS SNPs was performed by the polymerasechain reaction assay with TaqMan probes. The replicated positive associations wereconfirmed in another independent population.
[Results]
1. Associations between GWAS suggested genetic variants and stroke risk in Chinesewomen
The results showed that SNPs rs9943582, rs10958409, rs1333040, and rs10986769were associated with the risk of stroke. SNPs rs10958409and rs1333040wereassociated with increased risk of hemorrhagic stroke with adjusted ORs of1.83(95%CI1.12-3.01) and4.57(95%CI1.38-15.09), respectively, under dominant model.
In another independent population, only the association between rs1333040andstroke was verified. Risk T allele carriers of rs1333040were demonstrated to beassociated with a2.41-fold increased risk of stroke when compared with thenon-carriers.
The results from the pooled samples suggested the associations between two SNPs(rs10958409and rs1333040) and stroke (overall stroke and ischemic/hemorrhagicsubtypes) in Chinese women.
2. Joint effects between individual SNP: None.
3. Joint effects between COC use and genetic variants on stroke riskCompared with non-users without genetic variant, COC users carried geneticvariants of rs10958409or rs1333040significantly increased the risk of stroke,especially hemorrhagic stroke. COC use combined with genetic variants ofrs10958409or rs1333040increased the risk of hemorrhagic stroke by4.81-and 15.06-fold, respectively. The joint effects were noticeable in younger subjects (<50years).[Conclusion] SNPs rs10958409and rs1333040were confirmed to be associated withthe risk of stroke and its subtypes in Chinese women. COC use combined with thesegenetic variants significantly increased the risk of stroke, especially hemorrhagicsubtype.
在COC相关的健康风险中，脑卒中一直受到研究者的关注。中国是脑卒中高发国家，随着人口老龄化的加速和生活方式的改变，由脑卒中带来的健康和社会问题将愈加凸显。中国人群在脑卒中的发病率、表型、特征和风险因素等方面和欧美人群有着明显的不同，因此了解中国妇女服用COC等与脑卒中的关联及其特征将有助于更好地在中国女性人群中预防脑卒中的发生。
脑卒中是由环境因素和遗传因素共同作用所产生的复杂性疾病。环境因素仅能解释部分脑卒中事件的发生，比如同样服用COC的妇女仅有一小部分发生脑卒中，因此不同的个体对于脑卒中存在遗传易感性的差异。近年来，分析全基因组范围内遗传变异与疾病之间关联的全基因组关联研究（genome-wideassociation studies，GWAS）成为复杂疾病遗传机制研究的重要策略。随着GWAS的开展，越来越多的新的与脑卒中易感性相关联的单核苷酸多态性（singlenucleotide polymorphism，SNP）位点被报道。但是现有的脑卒中GWAS多在欧美人群中进行，中国人群与欧美人群相比等位基因频率存在着差异，那么在中国人群中能否重现这样的关联是一个值得探究的问题。
此外，风险因素之间的交互作用在复杂疾病的发生中亦发挥着重要的作用。研究发现，有偏头痛的妇女，如果同时使用口服避孕药或有高血压史或吸烟，将显著增加与之相关的梗塞型脑卒中的发病风险；服用COC联合凝血系统或肾素-血管紧张素系统基因多态会显著增加脑卒中的风险。因此探讨基因-基因和基因-环境因素之间的交互作用对于进一步阐明脑卒中的发病机制具有重要意义。
本研究是建立在国家科技攻关课题“避孕药长期应用安全性研究”前瞻性研究基础上的病例-对照研究，采用传统流行病学和分子流行病学相结合的研究手段，探讨与中国女性脑卒中相关联的风险因素，包括调查COC使用等环境因素和验证GWAS报道的易感SNPs，并探讨环境因素之间、遗传因素之间及环境-遗传因素之间的交互作用，为指导安全避孕提供科学依据，为防治脑卒中、促进女性健康提供有力保障。
第一部分口服避孕药与中国女性脑卒中发病风险的关联研究
口服避孕药是世界范围内广泛使用并且有效的避孕措施之一，目前全球范围内8.8%的育龄妇女口服避孕药进行避孕。虽然中国服用COC妇女的相对人数低于欧美国家，但是由于我国育龄妇女人数众多，故其绝对人数庞大，国产COC自20世纪70年代推广应用以来，曾经使用人数累计达数千万之多。为保证广大育龄妇女的健康，我国在降低COC中雌激素剂量和更新换代方面做了大量研究工作，但是缺乏国产低剂量COC与脑卒中等心脑血管疾病风险的远期安全性研究。
[目的]探讨COC使用等环境因素与中国妇女脑卒中发病风险之间的关联，探讨环境因素之间的交互作用对脑卒中发病风险的影响。
[方法]在对女性避孕药具使用人群随访的基础上前瞻性收集确诊的脑卒中新发病例，并按年龄和地区匹配健康对照和医院对照各一名。对服用COC等风险因素进行流行病学调查，测量血压、身高、体重，并采集空腹静脉血进行脂代谢测定。
[结果]
1. COC使用与中国女性脑卒中发病风险的关联服药妇女发生脑卒中的风险是未服药者的1.56倍。与未服药者相比，COC当前使用者发生脑卒中的风险增加3.05倍，而过去服用COC仅轻度增加脑卒中的发病风险。脑卒中的发病风险随着累计服药时间的延长而增加。此外，服用COC显著增加出血型脑卒中的发病风险，其年龄调整OR值为2.23（95%CI1.43-3.48），但与梗塞型脑卒中之间无统计学关联。
2中国女性脑卒中影响因素的多因素分析脑卒中家族史、服用COC、高血压、高血脂、糖尿病是脑卒中发生的风险因素；出血型脑卒中的风险因素为脑卒中家族史、服用COC、高血压、糖尿病；而梗塞型脑卒中的风险因素为年龄、脑卒中家族史、高血压、高血脂、糖尿病；人群中绝大部分脑卒中归因于高血压的发生。
3.风险因素之间的交互作用对脑卒中发病的影响高血压联合脑卒中家族史使脑卒中的发病风险增加21倍；高血压联合高血脂使梗塞型脑卒中的发病风险增加35倍；COC使用联合高血压使出血型脑卒中的发病风险增加18倍，均表现为相加的交互作用。[结论]服用COC是中国女性脑卒中的风险因素，且高血压与COC使用、高血脂、脑卒中家族史等风险因素之间的交互作用显著增加脑卒中的发病风险。
第二部分基于GWAS的遗传变异与中国女性脑卒中发病风险的关联研究
高血压等传统风险因素仅能解释部分脑卒中事件的发生，不同个体之间存在着遗传易感性的差异。近年来日益兴起的GWAS研究提示一些新的易感SNPs与脑卒中的发生之间有着密切的关联。但是目前已有的脑卒中GWAS研究多在欧美人群中进行，中国人群与欧美人群相比，无论在脑卒中亚型特征还是遗传特质方面均有着较大差异，比如，中国人群中出血型脑卒中所占比例较欧美人群高，等位基因的频率分布也与欧美人群有着较大差异。在中国人群中能否重现脑卒中GWAS研究已报道的阳性关联是一个值得探究的问题。
[目的]探讨脑卒中GWAS报道的遗传变异与中国女性脑卒中发病风险之间的关联，并探讨可能的基因-基因和基因-环境因素（COC使用）的交互作用。
[方法]采集脑卒中新发病例和对照的血标本，蛋白酶K消化后采用酚-氯仿法提取基因组DNA，采用PCR TaqMan探针技术对所选位点进行检测分型。对于检测到的阳性位点通过另一独立样本进行验证。
[结果]
1.基于GWAS的遗传变异与中国女性脑卒中发病风险的关联SNPs位点rs9943582、rs10958409、rs1333040、rs10986769遗传变异与脑卒中的发病风险相关联。rs10958409和rs1333040位点的遗传变异主要增加出血型脑卒中的发病风险，在显性模型下，其调整后的OR值分别为1.83（95%CI1.12-3.01）和4.57（95%CI1.38-15.09）。
在验证人群中仅发现rs1333040位点T等位基因携带者发生脑卒中的风险是未携带者的2.41倍。
合并分析结果显示，rs10958409和rs1333040位点遗传变异与中国女性脑卒中及其亚型相关联。
2. SNPs位点之间的联合作用分析：未发现多态位点之间存在联合作用。
3. COC使用联合遗传变异与脑卒中发病风险的关联妇女服用COC联合rs10958409或rs1333040位点遗传变异显著增加脑卒中尤其是出血型脑卒中的发病风险。与不服药且未携带风险等位基因的妇女相比，COC使用联合rs10958409或rs1333040位点遗传变异分别使出血型脑卒中的发病风险增加4.81倍和15.06倍，并且联合作用对脑卒中发病的影响在年龄<50岁的女性中尤为明显。
[结论] SNPs位点rs10958409和rs1333040遗传变异与中国女性脑卒中及其亚型相关联，且该遗传变异联合COC使用显著增加脑卒中尤其是出血型脑卒中的发病风险。
Use of oral contraceptives is considered as an innovative method for contraceptionin human beings. Combined oral contraceptives (COC) are combined estrogen andprogesterone. Clinical practice has demonstrated that COC use is one of the mosteffective and safest short-effect contraception methods for reducing unexpectedpregnancy. However, increased risk of cardio-cerebrovascular diseases such as stroke,myocardial infarction, and venous thromboembolism was reported to be associatedwith COC use since it was on the market in the developed countries in1960s.Although the development of low estrogen doses and altered progestin levels led tofewer cardio-cerebrovascular complications, the increased risk was still documentedin subsequent studies.
More attention has been paid to stroke among all COC related health risks. Theincidence of stroke is much higher in Chinese population. Moreover, with theacceleration of an aging population and changed lifestyle, health and social problemsarising from stroke will be more prominent. Compared with Caucasians, Chinesediffer in incidence rate, phenotypes, clinical characteristics, and risk factors of stroke.Therefore, to explore the associations between COC use and stroke risk will benefitfor stroke prevention in Chinese women.
Stroke is believed to be a kind of complex diseases arising from multiple environmental and genetic factors. Nevertheless, environmental factors could merelyexplain a small part of stroke, for instance, only a few of COC users suffer fromstroke. Therefore, there are differences in genetic susceptibilities in individuals whenthey are exposed to similar environmental factors. Recently, genome-wide associationstudies (GWAS) which analyze the genetic variants covering whole genome havebecome a promising method for the studies of genetic susceptibilities. With theadvances of GWAS, many new single nucleotide polymorphisms (SNPs) werereported to be associated with stroke risk. However, most of these GWAS of strokewere conducted in Caucasians. It is known there is difference of allelic frequencybetween Caucasians and Chinese. Therefore, it is an interesting topic to check theassociations between GWAS SNPs and the risk of stroke in Chinese population.
The interactions between risk factors may have an impact on the development of acomplex disease. Studies showed that in migrainous women, coexistent use of oralcontraceptives or a history of high blood pressure or smoking had greater thanmultiplicative effects on the odds ratios for ischemic stroke associated with migrainealone. In addition, the risk of stroke was significantly elevated in combination ofCOC use with gene polymorphisms of coagulation system and rennin-angiotensinsystem. To explore the possible gene-gene and gene-environment interactions willhelp in elucidating the mechanisms for stroke.
This study was a case-control study based on the prospective cohort which wasestablished with the support of National Key project ‘Study on the long term healtheffects of contraceptives’. Traditional epidemiological and molecular epidemiologicalmethods were applied integratedly in this study. The risk factors for stroke in Chinesewomen, including environmental factors such as COC use, and genetic variantssuggested by GWAS were investigated. Furthermore, the gene-gene andgene-environment interactions were discussed. The results from this study will behelpful in instructing contraceptive use, preventing stroke, and promoting women’shealth.
Part Ⅰ
COC Use and the Risk of Stroke in Chinese Women
COC is a widely used and effective method for contraception. About8.8%women of childbearing age take COC for contraception. Although there are a relativefew women taking COC in China, compared with those in developed countries, thetotal COC users are with a large number due to many women at reproductive age.Moreover, the accumulated number of women who have ever taken domestic-madeCOC since1970s is more than tens of millions. Many studies have been conducted toreduce estrogen doses and change the formulation of COC so as to protect women’shealth, however, there is few study on the long-term health effects related todomestic-made low-dose COC.
[Objective] To illuminate the associations between stroke and environmental factors(COC use) in Chinese women, and explore the possible interactions between theseenvironmental factors.
[Methods] On the basis of a prospective female cohort of contraceptive use, thefirst-ever stroke cases, as well as, two age-and region-matched controls (includingneighbourhoods and hospitalized patients) were recruited. An epidemiologicalinvestigation was conducted to obtain relevant information on possible risk factors,for instance, COC use. Blood pressure, height, and body weight were measured.Peripheral venous blood was taken for lipid tests after an overnight fast.
[Results]
1. The association between COC use and stroke risk in Chinese womenCOC users had a1.56-fold increased risk of stroke, compared with the non-users.Current COC use increased stroke risk by3.05-fold, while past use only slightlyincreased the risk. The stroke risk gradually elevated with the increasing cumulativetime of COC use. Moreover, COC use was significantly associated not with ischemicstroke but with hemorrhagic stroke subtype (OR2.23,95%CI1.43-3.48).
2. Analyses of risk factors for stroke in Chinese women
The risk factors for stroke included family history of stroke, COC use,hypertension, hyperlipidemia, and diabetes mellitus. Family history of stroke, COCuse, hypertension, and diabetes mellitus were risk factors for hemorrhagic stroke.While age, family history of stroke, hypertension, hyperlipidemia, and diabetesmellitus were risk factors for ischemic stroke. Most of the stroke could be attributableto hypertension.
3. Interactions between risk factors on stroke risk
Compared with normotensive women without family history of stroke,hypertensive women with family history of stroke had a22-fold increased risk ofstroke. In combination of hypertension and hyperlipidemia increased the risk ofischemic stroke by35-fold. COC use combined with hypertension elevated the risk ofhemorrhagic stroke by18-fold. Additive interactions between these risk factors weredetected.
[Conclusion] COC use was the risk factor for stroke in Chinese women. Theinteractions between hypertension and other risk factors (COC use, hyperlipidemia,family history of stroke) significantly increased the risk of stroke.
Part ⅡGWAS Suggested Genetic Variants and the Risk of Stroke in Chinese Women
Only a part of stroke could be attributed to the traditional risk factors such ashypertension. Genetic susceptibility does differ in individuals. Recently growing areaof GWAS has suggested several new SNPs associated with stroke risk. Nevertheless,most of these GWAS were conducted in Caucasians. There are differences in strokesubtypes and genetic characteristics when compared Chinese with Caucasians. Thepercentage of hemorrhagic stroke among overall stroke is higher in Chinese,compared with that in Caucasians. Furthermore, there are differences in thedistributions of allelic frequency. It is unknown if these positive associations reportedby GWAS of stroke in Caucasians could be replicated in Chinese.
[Objective] To demonstrate the associations between genetic variants suggested by GWAS and stroke risk in Chinese women, and explore the possible gene-gene andgene-environment (COC use) interactions.
[Methods] Blood samples were taken from first-ever stroke cases and controls.Genomic DNA was extracted by proteinase K digestion and phenol-chloroformextraction. Genotyping of selected GWAS SNPs was performed by the polymerasechain reaction assay with TaqMan probes. The replicated positive associations wereconfirmed in another independent population.
[Results]
1. Associations between GWAS suggested genetic variants and stroke risk in Chinesewomen
The results showed that SNPs rs9943582, rs10958409, rs1333040, and rs10986769were associated with the risk of stroke. SNPs rs10958409and rs1333040wereassociated with increased risk of hemorrhagic stroke with adjusted ORs of1.83(95%CI1.12-3.01) and4.57(95%CI1.38-15.09), respectively, under dominant model.
In another independent population, only the association between rs1333040andstroke was verified. Risk T allele carriers of rs1333040were demonstrated to beassociated with a2.41-fold increased risk of stroke when compared with thenon-carriers.
The results from the pooled samples suggested the associations between two SNPs(rs10958409and rs1333040) and stroke (overall stroke and ischemic/hemorrhagicsubtypes) in Chinese women.
2. Joint effects between individual SNP: None.
3. Joint effects between COC use and genetic variants on stroke riskCompared with non-users without genetic variant, COC users carried geneticvariants of rs10958409or rs1333040significantly increased the risk of stroke,especially hemorrhagic stroke. COC use combined with genetic variants ofrs10958409or rs1333040increased the risk of hemorrhagic stroke by4.81-and 15.06-fold, respectively. The joint effects were noticeable in younger subjects (<50years).[Conclusion] SNPs rs10958409and rs1333040were confirmed to be associated withthe risk of stroke and its subtypes in Chinese women. COC use combined with thesegenetic variants significantly increased the risk of stroke, especially hemorrhagicsubtype.
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