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

Abstract

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.

Guidelines for the Prevention of Stroke in Women

“…A recent casecontrol study of Chinese women evaluated the association between the single-nucleotide polymorphisms rs10958409 GA/AA (located near SOX17, a transcription factor that modulates cardiovascular development and endothelial cell biology) and rs1333040 CT/TT (located near CDKN2A, CDKN2B, and ANRIL, which regulate p53 activity) and risk of ischemic and hemorrhagic stroke in OC users and nonusers. 222 Women with the rs10958409 GA/AA or rs1333040 CT/TT genotypes (associated with susceptibility of intracranial aneurysm) had an increased overall risk of stroke, which increased to an OR of 6.06 (95% CI, 1.69-21.81) and 14.48 (95% CI, 1.56-134.43), respectively, in OC users <50 years of age. The rs1333040 single-nucleotide polymorphism was a significant risk with OC use only for hemorrhagic stroke, not IS.…”

“…The rs1333040 single-nucleotide polymorphism was a significant risk with OC use only for hemorrhagic stroke, not IS. 222 This study is important because it demonstrates not only the gene-drug interaction but also some potential mechanisms for how OCs might lead to hemorrhage in specific atrisk populations.…”

INTERMACS Analysis of Stroke During Support With Continuous-Flow Left Ventricular Assist Devices

“…(22) Specific single nucleotide polymorphisms can increase susceptibility to hemorrhagic strokes in association with OCs. (23) In post-menopausal women, aggregate data suggests that hormone replacement may slightly increase the risk of ischemic but not hemorrhagic stroke. (21) Sex hormone-independent mechanisms are also implicated, and there are differences in X-chromosome gene expression in men compared with women with ischemic stroke.…”

Associations between Aquaglyceroporin Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

“…Genomic DNA was extracted by proteinase K digestion and phenol–chloroform extraction [28]. Five SNPs (rs2989924, rs3758269, and rs62542743 in AQP7 ; rs57139208 and rs16939881 in AQP9 ) were selected as candidates because they were (1) potentially functional (nonsynonymous variants or variants in promoter region/5'-UTR/3'-UTR) or significantly associated with T2DM/obesity in previous reports; (2) with a minor allele frequency ≥ 5% in Han Chinese population.…”

“…Five SNPs (rs2989924, rs3758269, and rs62542743 in AQP7 ; rs57139208 and rs16939881 in AQP9 ) were selected as candidates because they were (1) potentially functional (nonsynonymous variants or variants in promoter region/5'-UTR/3'-UTR) or significantly associated with T2DM/obesity in previous reports; (2) with a minor allele frequency ≥ 5% in Han Chinese population. Genotyping of these SNPs was performed by the polymerase chain reaction assay with TaqMan probes in ABI Prism® 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions [28]. Allelic discrimination was automatically completed using the Sequence Detection Systems 2.3 software.…”