COMMENTARIES

Estrogen Receptor Alpha Gene and Cerebrovascular Disease

Sofia Markoula, M.D.1 and Ioannis Georgiou, Ph.D.2, 1Consultant Neurologist, Dept of Neurology, Ioannina University Hospital, 2Associate Professor of Medical Genetics, Medical Genetics Unit, Ioannina University Hospital, Ioannina 451 10 Greece

The role that reproductive steroids play in cerebrovascular pathophysiology and ischemia is an important area of ongoing investigation. Estrogens have vasoprotective properties against atherosclerosis [1] that are mediated through activation of specific estrogen receptors [2]. Vascular endothelial and smooth muscle cells contain estrogen receptor alpha protein [1,3]. Estrogen receptor alpha is a ligand-activated transcription factor influencing the regulation of cellular pathways and believed to mobilize signals at the plasma membrane and in the cytoplasm of the vessel wall cells.

          Experimental evidence from estrogen receptor alpha gene (ESR1) knockout mice showed that ESR1 mediates the ability of estradiol to protect the brain against injury [4]. Further data provide a potential mechanism by which estradiol exerts its protective role, by up-regulating ESR1 expression [5]. Furthermore, ESR1 gene mediates three direct effects of estrogen on the vessel wall on: a) nitric oxide production, b) the inhibition of vascular injury response and c) the re-endothelialization. ESR1 variations may associate with important estrogen-dependent characteristics such as coronary reactivity, coronary heart disease [6-8], myocardial infarction [9-11], responses to the lipid profile [2], and atherosclerotic severity to hormone replacement therapy [4].

In the recent literature there are many studies examining the association of polymorphisms of the ESR1 gene and in particular the association of c.454-397T>C and c.454-351A>G polymorphisms with cardiovascular disorders and stroke with conflicting results. Referring to coronary heart disease and myocardial infarction, an increased incidence of ischemic heart disease in patients carrying the c.454–397T and c.454–351A ESR1 haplotypes is demonstrated [9]. A protective property of c.454-397C allele in the cardiovascular system of postmenopausal women [12] but not of men is also described [13].

In particular, the Framingham study [14], a prospective study of 1,739 unrelated men and women, demonstrates an increase of atherothrombotic cardiovascular disease in men with CC genotype. A similar study, including more than 7,000 white men [10], provides evidence that CC genotype is a risk factor for nonfatal acute myocardial infarction. In contrast, results from the Rotterdam study [9], do not support this association, nor do two other studies of 5,063 and 3,657 participants, respectively [11,15].

Nevertheless, the Rotterdam study using diplotype analysis [9] demonstrates that the postmenopausal women who carry the ESR1 TTAA diplotype, but not men, have an increased risk of myocardial infarction and ischemic heart disease. Heterozygous carriers of this diplotype have 2.23 times increased risk of myocardial infarction compared to non-carriers, whereas homozygous carriers had 2.48 times increased risk. Diplotype analysis by Koch et al. does not verify associations [11].

Regarding ESR1 and stroke, in a study of 2,709 men of Shearman et al. [16], a higher risk for stroke is demonstrated in those with the CC genotype than in patients with CT or TT genotypes (RR, 1.92; 95% CI, 1.06 to 3.48). This association between ESR1 haplotype carriership and risk of ischemic stroke is not confirmed by a prospective population-based study by Bos et al. [17] during an average follow-up time of 10.1 years.

In other studies, although no direct association between ESR1 polymorphisms and ischemic stroke is found, several important gender-specific associations are surfaced [18-20] as a significantly increased risk of intracranial hemorrhage (ICH) in carriers of c.454-397T/T genotype, remaining in men but not in women after gender stratification [18]. The association of c.454-351A/A genotype of c.454-351A>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 is demonstrated in a study by our group [19,20]. The lower CC genotype in female patients suggests that the potentially lower ESR1 expression caused by the presence of the T allele at the -397 site may lead to a higher susceptibility to stroke, in analogy to a higher susceptibility to myocardial infarction in female patients with the T allele in the Rotterdam study [9]. In support of these findings there is recent evidence that ESR1 c.454-397C allele results in a relatively high level of ESR1 gene transcription [9], whereas the A allele at the -351 polymorphic site may lead to lower ESR1 expression, causing a higher susceptibility to stroke.

Additionally, a diplotype analysis in our study [19,20] shows that male patients have more frequently the CCGG diplotype than female patients (p = 0.03), while there is 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. From this diplotype analysis, it is also demonstrated that female patients with TTAA diplotype tend to have a higher stroke incidence compared to females with other diplotypes comparable with the results from the Rotterdam, associating TTAA with myocardial infarction in women [9].

All these studies underscore a potentially important role of ESR1 in influencing the development of atherosclerosis and in accelerating the transition from subclinical atherosclerosis to plaque rapture and acute thrombotic cardiovascular events, such as myocardial infarction and stroke. Gender-specific differences in the incidence of coronary artery disease, stroke, and generally in the development of atherosclerosis are attributable to the indirect effect of estrogen on risk factor profiles, such as cholesterol levels, glucose metabolism, and insulin levels [21]. Since several studies [9,12-14,18-20], included here, demonstrate a gender-specific impact of ESR1 on the development of cardiovascular and cerebrovascular disease, their findings should be considered as the consequence of different levels of circulating estrogens and gonadal steroids in males and females. A further exploration of possible gender-specific effects of ESR1 polymorphisms in the development of stroke is needed, especially for the ages at risk for cardiovascular and cerebrovascular events. Consequently, understanding of the estrogenic action and regulation may lead to the development of specific therapeutic agents that will mediate the prevention and treatment of vascular diseases, such as coronary heart disease and stroke.

References

  1.    Pare G, Krust A, Karas RH, et al. 2002. Estrogen receptor mediates the protective effects of estrogen against vascular injury. Circ Res 90: 1087-92.
  2.    Herrington DM, Howard TD, Hawkins GA, et al. 2002. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 346: 967-74.
  3.    Mendelsohn ME, Karas RH. 1999. The protective effects of estrogen on the cardiovascular system. N Engl J Med 340: 1801-11.
  4.    Dubal DB, Zhu H, Yu J, et al. 2001. Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A 98(4): 1952-57.
  5.    Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. 1999. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19(15): 6385-93.
  6.    Lehtimaki T, Laaksonen R, Mattila KM, et al. 2002. Estrogen receptor gene variation is a determinant of coronary reactivity in healthy young men. Eur J Clin Invest 32: 400-404.
  7.    Lehtimaki T, Kunnas TA, Mattila KM, et al. 2002. Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med 80: 176-80.
  8.    Almeida S, Hutz MH. 2006. Estrogen receptor 1 gene polymorphisms and coronary artery disease in the Brazilian population. Braz J Med Biol Res 39: 447-54.
  9.    Schuit SC, Oei HH, Witteman JC, et al. 2004. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. JAMA 291: 2969-77.
  10.    Shearman AM, Cooper JA, Kotwinski PJ, et al. 2006. Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ Res 98(5): 590-92.
  11.    Koch W, Hoppmann P, Pfeufer A, Mueller JC, Schomig A, Kastrati A. 2005. No replication of association between estrogen receptor a gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent. Circulation 112: 2138-42.
  12.    Herrington DM, Howard TD, Hawkins GA, et al. 2002. Estrogen-receptor polymorphisms and effects of estrogen replacement on high density lipoprotein cholesterol in women with coronary disease. N Engl J Med 346: 967-74.
  13.    Shearman AM, Cupples LA, Demissie S, et al. 2003. Association between estrogen receptor gene variation and cardiovascular disease. JAMA 290: 2263-70.
  14.    Shearman AM, Cupples LA, Demissie S, et al. 2003. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA 290: 2263-70.
  15.    Kjaergaard AD, Ellervik C, Tybjaerg-Hansen A, et al. 2007. Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture. Circulation 115: 861-71.
  16.    Shearman AM, Cooper JA, Kotwinski PJ, et al. 2005. Estrogen receptor alpha gene variation and the risk for stroke. Stroke 36: 2281-82.
  17.    Bos MJ, Schuit SCE, Koudstaal PJ, Hofman A, Uitterlinden AG, Breteler MMB. 2008. Variation in the estrogen receptor gene and risk of stroke. The Rotterdam Study. Stroke 39: 1324-26.
  18.    Strand M, Soderstrom I, Wiklund PG, et al. 2007. Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage. Cerebrovasc Dis 24: 500-508.
  19.    Lazaros L, Markoula S, Xita N, et al. 2008. Association of estrogen receptor-alpha gene polymorphisms with stroke risk in patients with metabolic syndrome. Acta Neurol Scand 117: 186-90.
  20.    Markoula S, Lazaros L, Xita N, et al. Estrogen receptor alpha gene polymorphisms and stroke. Cerebrovascular Disease In press.
  21.    Ho KJ, Liao JK. 2002. Non-nuclear actions of estrogen: new targets for prevention and treatment of cardiovascular disease. Mol Interv 2(4): 219-28.

 

 

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