Increased risk of stroke in oral contraceptive users carried replicated genetic variants: a population-based case-control study in China.

Combined oral contraceptives (COC) use is a unique risk factor for stroke in women, and may modify the associations between genetic polymorphisms and stroke. To investigate whether the genetic variants identified in a recent genome-wide association study (GWAS) could be replicated in Chinese women, as well as, whether related risk was different in COC users, 451 stroke cases and 831 age- and region-matched controls were recruited from our cohort. Genotyping of 3 SNPs (rs700651, rs10958409, and rs1333040) was performed by the polymerase chain reaction assay with TaqMan probes. The history of contraceptive use and relevant information were obtained from a face-to-face interview. Odds ratios (OR) with 95 % confidence interval (CI) were estimated under conditional logistic regression model after adjustment for cardiovascular covariates. Our study replicated the associations of rs10958409 and rs1333040, with the risk of stroke, especially hemorrhagic subtype, but failed to confirm association of rs700651. COC use was associated with a 1.56-fold (OR 1.56, 95 % CI 1.21-2.01) increased risk of stroke. COC users with rs10958409 GA/AA or rs1333040 CT/TT genotypes had an increased risk of overall stroke by 1.59-fold (OR 2.59, 95 % CI 1.59-4.19) and 3.24-fold (OR 4.24, 95 % CI 1.71-10.49), respectively, compared with the non-users with wild-type genotypes. Moreover, the risk of hemorrhagic stroke increased by 4.81- and 15.06-fold when risk allele carriers of rs10958409 or rs1333040 who took COC. Our results confirmed the associations of two GWAS SNPs, also suggested combination effects of these genetic variants and COC use on stroke risk.

Pai-1 gene variants and COC use are associated with stroke risk: a case-control study in the Han Chinese women.

Genetic variants of plasminogen activator inhibitor type 1 (PAI-1) gene have been suggested to influence the PAI-1 transcription activity and PAI-1 levels as well as might be involved in the pathophysiology of stroke. The aims of this study are to investigate whether the polymorphisms at the PAI-1 gene are associated with the risk of stroke and to explore the combined effects of PAI-1 variants and combined oral contraceptive (COC) use for stroke risk. We conducted a nested case-control study using 453 first-ever female stroke cases and 919 age- and region-matched controls that were recruited from our prospective surveillance cohort. SNP rs1799889 was genotyped by allele-specific polymerase chain reaction (PCR), and SNPs rs7242 and rs2227631 were detected by the TaqMan SNP genotyping assay. We identified that rs1799889 5G allele conferred a protective effect against ischemic stroke while 4G allele conferred an increased risk of ischemic stroke. But we failed to suggest associations of rs7242 and rs2227631. COC users had a 1.31-fold (OR=1.31, 95% CI=1.01-1.71) increased risk of stroke compared with the non-users. Furthermore, COC users with rs1799889 4G5G/5G5G genotype had a decreased risk of ischemic stroke (OR=0.53, 95% CI=0.34-0.83). Moreover, haplotype G-5G-T was associated with an increased risk of overall stroke (OR=1.28, 95% CI=1.01-1.62). In contrast, haplotype A-4G-G and haplotype G-5G-T were slightly associated with the protection from ischemic stroke (OR=0.61, 95% CI=0.46-0.82; OR=0.61, 95% CI=0.44-0.85, respectively). The study assessed the associations of three PAI-1 SNPs and also suggested combined effects of these PAI-1 gene variants and COC use on stroke risk in the Han Chinese women.

[Study on the association of oral contraceptives, angiotensinogen gene polymorphisms and the risk of stroke in women].

OBJECTIVE: To evaluate the associations of oral contraceptives (OC) exposure, angiotensinogen (AGT) gene polymorphism and joint effects on the risk of stroke in Chinese women. METHODS: On the basis of a prospective female cohort of contraceptive use, the first-ever-developed (FED) stroke cases, as well as, two sets of age-(± 3 years) and region-matched controls (including neighborhoods and hospitalized patients) were recruited. Between 1 July 2000 and 30 June 2009, a total of 453 FED stroke cases and 919 controls were recruited. Genotyping for polymorphisms of AGT gene was detected by Taqman method. RESULTS: (1) The risk of stroke gradually increased with the cumulative time of OC use in women (P < 0.0001). Compared with the non-users, the risk of hemorrhagic stroke slightly increased among those with OC use (OR = 1.83, 95%CI: 1.25 - 2.66). (2) Women with AG/GG genotypes of A-6G locus or CA/AA genotypes of C11535A locus indicated that there was a slightly reduced risk of stroke (OR = 0.78, 95%CI: 0.61 - 0.99; OR = 0.73, 95%CI: 0.56 - 0.95). (3) Women with AA genotypes of A-20C locus and AG/GG genotypes of A-6G, when incorporated with CA/AA genotypes of C11535A locus with OC, it could increase the risk of 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). CONCLUSION: The AGT gene polymorphisms showed that they did have an impact on the risk of stroke. And the joint effect between women using OC and AGT gene polymorphisms could slightly increase the risk of stroke.

[Study on the association of oral contraceptives, angiotensin-converting enzyme gene polymorphisms and risk of stroke in women].

OBJECTIVE: To evaluate the associations of oral contraceptives (OC) exposure, angiotensin-converting enzyme (ACE) gene polymorphism and their joint actions with the risk of stroke in Chinese women. METHODS: A case-control study, based on a set cohort, was carried out. Incident cases of stroke identified between July 1 1997 and June 30 2009 were enrolled. One hospital control and healthy community control were matched on region and age (± 3 years). A total of 453 women with stroke and 919 controls were recruited. I/D gene polymorphism was detected by polymerase chain reaction (PCR) and amplification fragment length polymorphism (AFLP), A-240T polymorphism were detected by TagMan. RESULTS: (1) The risk of stroke gradually increased with the cumulative time of OC being used in women (P < 0.0001). Compared with non-users, the risk of stroke significantly increased among those with cumulative time of using OC longer than 20 years (adjusted OR was 2.07, with 95%CI as 1.30 - 3.29). (2) ID/DD genotype of I/D locus indicated significantly an increased risk of hemorrhagic stroke (adjusted OR, 2.37; 95%CI, 1.46 - 3.84). (3) Women with ID/DD genotype of I/D locus or with TA/TT genotype of A-240T locus and using OC could significantly increase the risk of hemorrhagic stroke (adjusted OR was 4.59; with 95%CI as 2.21 - 9.51 and OR was 2.50; with 95%CI as 1.42 - 4.38). (4) Data from multivariate analyses showed that both OC and ID/DD genotypes were important risk factors for hemorrhagic stroke. CONCLUSION: ID/DD and TA/TT genotypes of ACE gene, OC and their joint action might increase the risk of stroke, especially on hemorrhagic stroke in Chinese women.