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Cardiovascular Disease and Estrogen Receptor Alpha Polymorphisms
October 21, 2004

Reviewed by:

Sabrina Cheng, M.D.
Pediatrics Genetics Team
NCBDDD, CDC, Atlanta

The Health Outcome

Cardiovascular disease (CVD) includes coronary heart disease (CHD) and stroke which are the leading causes of death and disability among adults (1). By 2020, CVD will claim 25 million deaths yearly and coronary heart disease will replace infectious disease as the world’s leading cause of death and disability (2). In the US, about 57 million Americans have some form of CVD and about 950,000 Americans die from it annually (3). About 1.1 million Americans suffer a heart attack (myocardial infarction, MI) each year with about half proving fatal (4). Although improvements in medical care and secondary prevention have led to decreased mortality from CHD for the past 30 years, the rate of decline is slowing down (3) and the incidence of CHD has not declined (5). Heart disease and stroke cost the US nearly $260 billion annually (3).

Various genetic polymorphisms have been studied for association with cardiovascular disease. These include genes for thrombophilia, angiotensin-converting enzyme, lipid metabolism, inflammation, adrenergic receptors as well as apolipoprotein E.

The Finding

Shearman et al. (6) reported that the ESR1 c.454-397CC genotype is associated with increased odds of MI based on the results of a nested case-control study within the Framingham (MA) offspring cohort. 1811 DNA samples were genotyped, and 1739 men and women with the c.454-397T>C polymorphism were evaluated. The study compared people with the TT, TC, and CC genotypes. Of these 1739, 1561 served as controls for comparison with the 178 men and women who had CVD at the time of the sixth cohort follow-up examination in 1995-1998. Three CVD outcomes (total, major, acute MI) were examined (see abstraction template for details). The c.454-397CC genotype was associated with a 3-fold (CI: 1.7-5.2) increase in risk for MI using a fully adjusted recessive model with age, sex, body mass index, hypertension, diabetes mellitus, total and high-density lipoprotein cholesterol level, and smoking as covariates. Three other polymorphisms (c.30T>C, c.454-351A>G and c.975C>G) were evaluated for association with CVD with negative results. The authors concluded that the ESR1 c.454-397CC polymorphism increases risk for MI which persists after adjustment for traditional CVD risk factors. They caution that while their results support the importance of estrogen receptors in CVD susceptibility especially in men, further studies are needed to determine if these results can be generalized to other genetically distinct populations and to women. Larger studies would also be needed to assess gene-gene and gene-environment interactions.


Public Health Implications

Attributable fractions due to the ESR1 c.454-397CC genotype ranged from 0.05 for the major CVD group to 0.2 for the acute MI group. This finding is interesting because of the biologic plausibility for the role of this polymorphism in CVD, in addition to the significant morbidity and mortality associated with CVD. Additional and larger population-based studies, including genetically similar and distinct populations as well as larger numbers of female cases, for example post-menopausal women on and off hormone replacement therapy, should be pursued to investigate the relevance of this finding and to evaluate gene-environment and gene-gene interactions. Although this finding could ultimately help further our understanding regarding the pathophysiology underlying CVD and perhaps lead to better and improved therapies, it would not replace current prevention and medical management such as smoking cessation; treatment of hypertension and hyperlipidemia through diet, exercise, and medications; and management of diabetes which are known to exert significant reduction in risk of cardiovascular events for everyone, regardless of ethnicity and gender. These measures would still apply for individuals with the CC genotype. Thus, there is currently no public health justification for population-based screening.


References

  1. Truelsen T, Mahonen M, Tolonen H, Asplund K, Bonita R, Vanuzzo D. Trends in stroke and coronary heart disease in the WHO MONICA Project. Stroke 2003;34(6):1346-52.
  2. Gaziano, JM. Global burden of cardiovascular disease, chapter 1 in Braunwald.: Heart Disease: A Textbook of Cardiovascular Medicine, 6 th ed., W.B. Saunders Co, 2001.
  3. Centers for Disease Control and Prevention. Data fact sheet. Facts about cardiovascular disease. 1997. Atlanta, GA: U.S. Department of Health and Human Services.
  4. National Heart, Lung, and Blood Institute. Data Fact sheet. Facts about coronary heart disease.2003. Bethesda, MD: U.S. Department of Health and Human Services.
  5. Rosamond WD, Chambless LE, Folson AR, Cooper LS, Conwill DE, Clegg L, Wang CH, Heiss G.Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994. N Engl J Med. 1998;339(13):861-7.
  6. Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, LevyD. Association Between Estrogen Receptor {alpha} Gene Variation and Cardiovascular Disease. JAMA, 2003; 290(17): 2263 - 2270.
Last Updated October 22, 2004