Estrogen Receptor α Gene Haplotypes and Diplotypes in the Risk of Stroke
To the Editor:
We wish to comment on the retrospective population-based study by Bos et al,1 concerning the association between estrogen receptor α gene variations and the risk of stroke. During an average follow-up time of 10.1 years, the authors of this study did not find any association between ESR1 haplotype carriership and risk of ischemic stroke in 659 strokes occurred, of which 386 were ischemic.
We have recently investigated the possible association between ESR1 polymorphisms and ischemic stroke in patients with metabolic syndrome.2 One hundred and thirty patients with metabolic syndrome, 84 males and 46 females, hospitalized in the Stroke Reference Center of Northwest Greece from January 2003 to December 2005 were included in our prospective study. As controls, 240 healthy age-matched individuals, 100 men and 140 women were recruited without a history of stroke or metabolic syndrome. In our case-control study no direct association of PvuII and XbaI polymorphisms with ischemic stroke was identified in both genders, in accordance to Bos et al findings.2 However, further analysis lead to interesting findings, with the most significant being the association of c.454 to 351A/A genotype of c.454 to 351A>G polymorphism with the onset of stroke at a younger age in male patients (P<0.05), and the lower c.454-397C/C genotype frequency of 454-397T>C polymorphism in female patients with ischemic stroke compared to female controls.
Our results are in accordance with previously published reports that showed increased incidence of ischemic heart disease in patients carrying the c.454-351A allele ESR13 and the protective properties of c.454-397C allele in the cardiovascular system of postmenopausal women.4 These protective properties of c.454-397C allele have not been found in men, where the C allele is associated with stroke.5
A dissimilarity between the study by Bos et al and our study is the use of haplotypes in the first and diplotypes in the other. In the stroke study by Bos et al, the haplotypes used for analysis were reconstructed using the PHASE software which simulates and compensates for the lack of genetic material from the patients’ parents. In our study2 diplotype analysis was used, because diplotypes are unaffected by biases of reconstruction which may marginally or critically affect the results, although both approaches have equal capacity to reflect linkage disequilibrium between polymorphisms. Using diplotypes, we found that male patients had more frequently the CCGG diplotype than female patients (P=0.03), whereas there was no difference between healthy men and healthy women, suggesting that the CCGG diplotype makes men more sensitive to develop cardiovascular ischemic events compared to women.2 Additionaly, from this diplotype analysis, it was found that female patients with TTAA diplotype tended to have a higher stroke incidence compared to females with other diplotypes (36.9% versus 26.4%, P<0.1). In support of our findings, the Rotterdam study6 demonstrated that postmenopausal women who carry the ESR1 TTAA diplotype, but not men, have an increased risk of myocardial infarction and ischemic heart disease.
Gender-specific differences in the incidence of hypertension, coronary artery disease, stroke, or generally in the development of atherosclerosis are attributable to the indirect effect of estrogens on risk factor profiles.4 Because several studies,4,5,6 including ours, demonstrate a gender-specific impact of ESR1 on the development of stroke, these findings should be considered as the consequence of differences in the levels of circulating estrogens and gonadal steroidogenesis between males and females. However, larger controlled studies using diplotype analysis are needed for further exploration of gender-specific effects of the ESR1 polymorphisms in various stroke types.
Sources of Funding
This letter is part of the 03ED research project, implemented within the framework of the Reinforcement Programme of Human Research Manpower (PENED) and co-financed by National and Community Funds (25% from the Greek Ministry of Development-General Secretariat of Research and Technology and 75% from E.U.-European Social Fund).
Bos MJ, Schuit SCE, Koudstaal PJ, Hofman A, Uitterlinden AG, Breteler MMB. Variation in the estrogen receptor gene and risk of stroke: The Rotterdam Study. Stroke. 2008; 39: 1324–1326.
Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER. Estrogen-receptor polymorphisms and effects of estrogen replacement on high density lipoprotein cholesterol in women with coronary disease. N Engl J Med. 2002; 346: 967–974.
Shearman AM, Cooper JA, Kotwinski PJ, Humphries SE, Mendelsohn ME, Housman DE, Miller GJ. Estrogen receptor alpha gene variation and the risk for stroke. Stroke. 2005; 36: 2281–2282.