Estrogen receptor α genetic variants and the risk of stroke in a South Indian population from Andhra Pradesh.
ABSTRACT Stroke is a complex disease caused by combination of multiple risk factors. Recent findings have suggested that stroke has a strong genetic component. Evidence suggests that variations in the estrogen receptor α (ESR1) gene may influence stroke risk.
The present study was carried out to investigate the role of ESR1 gene polymorphisms [PvuII (rs 2234693) and XbaI (rs 9340799)] with stroke in a South Indian population from Andhra Pradesh. The relationship between ESR1 genotypes with estradiol levels was also investigated in pre- and postmenopausal women.
Four hundred patients with ischemic stroke and three hundred and eighty subjects were enrolled in this case-control study. Ischemic stroke subtypes were classified according to TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. The ESR1 PvuII and XbaI genotypes were determined by PCR-RFLP method. Serum estradiol was measured by ELISA.
In case of PvuII polymorphism statistically significant difference was observed in the genotypic and allelic frequencies between patients and controls (joint analysis of men and women) (p=0.003 and 0.004 respectively). However, the XbaI genotypes and alleles did not show an association with stroke in the study population. When the analysis was carried out separately for men and women, the PvuII polymorphism did not show significant association with stroke in men; women showed a significant association. Further when women were grouped in to premenopausal and postmenopausal, the premenopausal group did not show a significant association with the polymorphism but significant association with stroke was found in postmenopausal women. A stepwise multiple logistic regression analysis confirmed these findings. Women with pp genotype had low estradiol levels in comparison with PP genotypic individuals (p<0.05). Further evaluating the association of this polymorphism with stroke subtypes, we found significant association of PvuII polymorphism with extracranial atherosclerosis, lacunar and cardioembolic stroke.
In conclusion our results suggest the PvuII gene polymorphism is significantly associated with stroke in postmenopausal women in a South Indian population from Andhra Pradesh. The pp genotypes have average 17β estradiol levels which are significantly low in comparison with PP genotypes. Therefore postmenopausal women with a high frequency of pp genotype are more predisposed to ischemic stroke. However, this is a preliminary study and the results need to be confirmed in a larger cohort.
- [Show abstract] [Hide abstract]
ABSTRACT: A number of studies have documented that estrogen receptor α (ESR1) may play an important role in the development and progression of cerebral infarction, but many existing studies have yielded inconclusive results. This meta-analysis was performed to evaluate the relationships between ESR1 genetic polymorphisms and cerebral infarction risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before October 1, 2013, without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Seven case-control studies were included with a total of 1471 patients with cerebral infarction and 4688 healthy control subjects. Two common single-nucleotide polymorphisms (SNPs) in the ESR1 gene (rs2234693 T>C and rs9340799 A>G) were assessed. Our meta-analysis results revealed that ESR1 genetic polymorphisms might increase the risk of cerebral infarction. Subgroup analysis by SNP type indicated that both rs2234693 and rs9340799 polymorphisms in the ESR1 gene were strongly associated with an increased risk of cerebral infarction. Further subgroup analysis by ethnicity showed significant associations between ESR1 genetic polymorphisms and increased risk of cerebral infarction among both Asians and Caucasians. In the stratified subgroup analysis by gender, the results suggested that ESR1 genetic polymorphisms were associated with an increased risk of cerebral infarction in the female population. However, there were no statistically significant associations between ESR1 genetic polymorphisms and cerebral infarction risk in the male population. Meta-regression analyses also confirmed that gender might be a main source of heterogeneity. Our findings indicate that ESR1 genetic polymorphisms may contribute to the development of cerebral infarction, especially in the female population.DNA and cell biology 04/2014; · 2.28 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background: In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor alpha (ESR1) and beta (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated. Methods: In the Three-City prospective cohort study among subjects over 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17β-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4-year of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for 1-standard deviation increase in hormones levels by genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and correction for multiple testing. We also investigated the role of haemostasis and inflammation as potential mediators. Results: Neither estrogens nor IAD risk were significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol (HR:1.40, 95%CI:1.11-1.77). Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with AG/GG genotype (HR:1.62, 95%CI:1.22-2.17 and HR:1.03, 95%CI:0.81-1.30, respectively; p for interaction<0.05). Additional adjustment for haemostatic variables reduced the HR by about one third in women carrying rs9340799-AA genotype (HR:1.41, 95%CI:1.06-1.90). Conclusion: ESR1 rs9340799 genotype may modify IAD risk related to high endogenous estrogens levels in older postmenopausal women. Hypercoagulability may act as a mediator.The Journal of Clinical Endocrinology and Metabolism 05/2014; · 6.31 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background: CCL11 (Eotaxin-1) is an important inflammatory cytokine belonging to the CC family of chemokines associated with a number of infection or inflammation-related diseases such as atherosclerosis and stroke. We investigated the association of CCL11 gene polymorphism rs4795895-1382A>G with ischemic and hemorrhagic stroke. Materials and Methods: Six hundred and twenty ischemic stroke patients, 620 age- and sex-matched healthy controls, and 220 hemorrhagic stroke patients, 220 age- and sex-matched healthy controls were included in the present study. The CCL11 gene polymorphism rs4795895-1382A>G was determined using PCR-RFLP technique. Results: We found a statistically significant difference in the genotypic distribution between ischemic stroke patients and controls (For GG vs. AA, χ2 = 7.604; P < 0.001, Odds ratio = 2.793; 95% CI = 1.308-5.9). For GG vs. AA + AG, χ2 = 44.8, P < 0.001, Odds ratio = 2.382 (95% CI = 1.842-3.081). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ2 = 43.26; P < 0.001, Odds ratio = 2.127; 95% CI = 1.693-2.672). Statistically significant difference was observed in the genotypic distribution between hemorrhagic stroke patients and controls (For GG vs. AG, χ2 = 26.78; P = 0.001, Odds ratio = 3.5; 95% CI = 2.162-5.824). A significant difference was observed in the frequency of G and A alleles in patients and controls (For G vs. A, χ2 = 41.98; P = 0.001, Odds ratio = 4.1; 95% CI = 2.61-6.44). Conclusion: The results of the present study show that the GG genotype is a significant risk factor for ischemic as well as hemorrhagic stroke. Further, the frequency of the GG genotype was observed to be higher in hemorrhagic stroke patients in comparison with ischemic stroke. Evaluating the association with ischemic stroke subtypes, a significant association was observed with intracranial large artery atherosclerosis and lacunar stroke.Neurology India 07/2014; 62(4):387-392. · 1.08 Impact Factor