Published online before print February 16, 2006, doi: 10.1161/01.RES.0000210578.62102.a6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Reports |
Estrogen Receptor 
Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts
From the Center for Cancer Research (A.M.S., D.E.H.), Massachusetts Institute of Technology, Cambridge, Mass; Center for Cardiovascular Genetics (J.A.C., P.J.K., S.E.H.), Department of Medicine, Royal Free and University College London Medical School, Rayne Institute, United Kingdom; Portex Anaesthesia, Intensive Therapy and Respiratory Medicine Unit (P.J.K.), Institute of Child Health, London, United Kingdom; Medical Research Council Cardiovascular Research Group (G.J.M.), Wolfson Institute of Preventive Medicine, London, United Kingdom; Genomics Collaborative (K.G.A., B.J., K.I., K.L.L.), Cambridge, Mass; Departments of Internal Medicine and Epidemiology & Biostatistics (S.C.E.S., A.G.U., H.A.P.P.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Biostatistics, Boston University School of Public Health (S.D., L.A.C.), Boston, Mass; Tufts–New England Medical Center (M.E.M.), Boston, Mass; and the Framingham Heart Study of the National Heart, Lung, and Blood Institute (D.L.), Framingham, Mass.
Correspondence to Dr Amanda M. Shearman, E17-536, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail shearman{at}mit.edu
Abstract
Understanding the mechanisms by which estrogens affect cardiovascular disease risk, including the role of variation in the gene for estrogen receptor 
(ESR1), may be key to new treatment strategies. We investigated whether the CC genotype at ESR1 c.454-397T>C is associated with increased risk among men. Study of more than 7000 whites in 5 cohorts from 4 countries provided evidence that genotype CC, present in roughly 20% of individuals, is a risk factor for nonfatal acute myocardial infarction (odds ratio=1.44; P<0.0001), after adjustment for established cardiovascular risk factors. After exclusion of younger subjects from 2 cohorts, because of age interaction, the odds ratio increased (to 1.63).
Key Words: genetics • myocardial infarction • estrogen receptor • risk factors
In the Rotterdam Study, an estrogen receptor (ESR1) haplotype, including the ESR1 c.454-397 T allele, also referred to in previous studies as the p allele of the PvuII site in intron 1 (rs2234693), was associated with significantly increased risk of myocardial infarction (MI) among postmenopausal women (for homozygous carriers, the relative risk was 2.48; the 95% confidence interval [CI], 1.22 to 5.03 after adjusting for known cardiovascular risk factors).1 In men, however, no statistically significant association was found (relative risk, 0.82; 95% CI, 0.49 to 1.38). These results may be viewed as at odds with previous reports by us and others of a significantly higher risk of MI among men with the c.454-397CC genotype (PP of PvuII).2,3 We aimed to clarify whether the CC genotype at ESR1 c.454-397T>C is associated with increased odds of nonfatal MI among men.
Materials and Methods
We included only cohorts of white men not recruited on the basis of coronary heart disease risk factors (Table I in the online data supplement, available at http://circres.ahajournals.org). We studied men from the prospective population-based Second Northwick Park Heart Study (NPHSII) in the United Kingdom4 and 2 case-control studies of MI from Poland and the United States, selected from the Global Repository at Genomics Collaborative.5 Here we present a metaanalysis of the results of these studies and published results from the Framingham3 and Rotterdam Studies1: a total of more than 7000 men with detailed covariate information, including 731 men with acute, nonfatal MI. We also carried out analyses of total MI, including 47 fatal MIs in NPHSII and the Rotterdam Study, and ischemic heart disease (IHD) in the 3 prospective studies. Unless specified, odds ratios (ORs) are from a fixed effects model, adjusted for age, body mass index, serum total cholesterol level, hypertension, diabetes, and smoking status.
Results
The mean (SD) values for age (supplemental Table I), body mass index, and total cholesterol level, as well as the prevalence of current smoking, hypertension, and diabetes were not significantly different by genotype. Comparing men with the ESR1 c.454-397CC genotype with those with CT or TT genotypes, pooled OR=1.44 (95% CI, 1.17 to 1.76; P<0.0001) for MI (Figure). Power was low for detection of an association with fatal MI, with 20% power to detect an effect of the size seen in the nonfatal MIs. Of 47 fatal MIs, only 4 (8.5%) had an ESR1 c.454-397CC genotype. When fatal MIs were included in the Rotterdam and NPHSII analyses, the ORs for total MI were 1.11 (95% CI, 0.72 to 1.71) and 1.23 (95% CI, 0.83 to 1.82), respectively, with the pooled OR 1.31 (95% CI, 1.07 to 1.59; P=0.008). After exclusion of total MI, the combined IHD result from the 3 prospective studies was not significant, pooled OR=0.90 (95% CI: 0.62 to 1.32; P=0.62). Almost identical results were obtained from analyses that were either adjusted or unadjusted. Using the fixed effects OR for nonfatal MI as the estimate of relative risk, the population-attributable risk was 6.4%. The test for heterogeneity was not significant (P>0.05) for any analysis. Results were still significant after exclusion of the Framingham Heart Study data that contributed the highest OR, with a pooled OR of 1.31 (95% CI, 1.05 to 1.62; P=0.015). Suggestive evidence of heterogeneity in the initial metaanalysis of the nonfatal MIs (P=0.07) was not present when the Framingham cohort or younger case-control subjects (where we found evidence of interaction between age and genotype in association with risk of MI; Figure) were excluded. There was interaction between age (>60 or <60 years) and genotype with respect to risk of MI in the Polish case-control study (P=0.05). ORs=2.11 (95% CI, 1.12 to 3.98; P=0.02) in the older and 0.95 (95% CI 0.59 to 1.53; P=0.83) in the younger subgroups. There was a similar trend in the US case-control study, the respective ORs being 1.59 (95% CI, 0.95 to 2.67; P=0.08) and 0.90 (95% CI 0.48 to 1.65; P=0.73), but here the interaction term was not significant (P=0.16). By contrast, there was no evidence for similar interaction in any of the 3 prospective studies. When the 5 studies were each subdivided by age (study-specific mean age of event in the case-control studies and study-specific mean baseline age in the prospective studies), metaanalysis restricted to the older or younger subgroup of each cohort gave OR=1.58 (95% CI 1.19 to 2.10; P=0.002) and 1.22 (95% CI 0.92 to 1.62; P=0.17), respectively. Justified by these findings, metaanalysis excluding the younger case-control subgroups gave OR=1.63 (95% CI 1.29 to 2.07; P<0.0001).
|
Discussion
Sixty-eight percent of the weight of our model for nonfatal MI is derived from previously unstudied cohorts, making it unlikely that our results have been affected by publication bias. Our findings also show consistency across 5 white cohorts from 4 countries, providing additional evidence that the association is real and not attributable to population stratification or a context dependent factor.6 There was wide variability in participant age across the 5 studies, and we obtained evidence that the association we report may be affected by subject age. That a time window of maximum effect exists for this ESR1 genotype (which may itself vary with characteristics such as ethnicity, diet, estrogen levels, and established risk factors for MI) would be compatible with previous results and recent negative findings from an MI case-control study of men with mean age in the early sixties (SD 12 years),7 and should be tested in other populations including studies of hormone replacement therapy.8 Fatality for MI may potentially be affected by ESR1 variation and the 2 case-control studies recruited only survivors of MI. Therefore, only nonfatal cardiovascular events were initially included in this metaanalysis. Secondary analyses including 47 fatal MIs provided results that were significant; however, only 8.5% of subjects with a fatal MI had an ESR1 c.454-397CC genotype. Although not statistically significant, there was a trend toward decreased risk of fatal MI in subjects with c.454-397CC genotype, in both studies that included such events. Although this initially appears to be at odds with the findings for nonfatal MIs, results from women in the Rotterdam Study1 included higher mortality in the year after IHD among women without c.454-397CC genotype. This is consistent with the highest OR being from the Framingham Study, where survival for blood sampling at the sixth examination cycle, almost 3 decades after the start of the study, was required for inclusion and might, in part, underlie the results we observe for nonfatal MIs. A genetic basis for increased risk of fatality among older subjects might be a reason for the observed interaction with age. Further studies of fatal MI are required to resolve whether the impact of the c.454-397CC genotype on nonfatal events differs from that on fatal events.1–3
Estrogen receptors are required for normal vascular physiology in males,9 although the underlying mechanisms are not clear. Several studies suggest that c.454-397C is within a potential transcription factor binding site and results in a relatively high level of ESR1 transcription as compared with c.454-397T.1,10 A study of postmenopausal women reported that c.454-397CC genotype was associated with more severe atherosclerosis at baseline than in other genotypes but progressed more slowly in response to hormone-replacement therapy.11 The alleles of a polymorphic TA repeat, in the ESR1 promoter, in strong linkage disequilibrium with c.454-397C, have been associated with more severely narrowed coronary arteries, larger areas of complicated lesions, and lower adenosine-stimulated myocardial blood flow.12–14 A more comprehensive evaluation of ESR1 is required to determine the mechanism(s) underlying these observed associations.
Our results add substantially to recent evidence that a mechanism based on ESR1 variation contributes to a range of important estrogen-dependent characteristics, including responses of the lipid profile to hormone replacement therapy and risk of fracture.15,16
For nonfatal MI events in the populations included in this study, the population risk attributable to the ESR1 c.454-397CC genotype was 6.4%, which would correspond among US men17 to approximately 25 000 of such events each year and incur substantial hospital and medical expenses.
Acknowledgments
Support was from the National Heart, Lung, and Blood Institute (Tufts–New England Medical Center Specialized Center of Research in Ischemic Heart Disease, P50-HL63494; the Framingham Heart Study contract N01-HC-25195; RO1-HL65230; HL-33014; and HL-54502), the Netherlands Organization for Scientific Research under the Research Institute for Diseases in the Elderly (grant 014-90-001), the Dutch Research Organization NWO (RIDE grant 14-93-015), the European Commission ("GENOMOS"; QLK6-CT-2002-02629), the UK Medical Research Council, the British Heart Foundation (RG 2000/015), and Du Pont Pharma, Wilmington, Del. The National Heart, Lung, and Blood Institute reviewed the manuscript for scientific content and consistency of data interpretation with previous Framingham publications. We are indebted to all those who participated in the studies and thank the anonymous reviewers for helpful suggestions.
Footnotes
Sera Care Life Science employed K.G.A., K.I., B.J., and K.L.L. and donated the DNA samples and data from the case control studies free of charge. M.E.M. had minor speakers bureau appointments at Wyeth and Merck and honoraria for academic talks. D.E.H., D.L., M.E.M., and A.M.S. were named on a patent application filed through the Massachusetts Institute of Technology technology licensing office for medical uses related to estrogen receptor gene variation.
Original received November 15, 2004; first resubmission received January 3, 2005; revised first resubmission received February 7, 2005; second resubmission received November 15, 2005; revised second resubmission received December 15, 2005; accepted February 3. 2006.
References
- Schuit SC, Oei HH, Witteman JC, Geurts van Kessel CH, van Meurs JB, Nijhuis RL, van Leeuwen JP, de Jong FH, Zillikens MC, Hofman A, Pols HA, Uitterlinden AG. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. JAMA. 2004; 291: 2969–2677.
[Abstract/Free Full Text] - Lehtimaki T, Kunnas TA, Mattila KM, Perola M, Penttila A, Koivula T, Karhunen PJ. Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med. 2002; 80: 176–180.[CrossRef][Medline] [Order article via Infotrieve]
- Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, Levy D. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA. 2003; 290: 2263–2270.
[Abstract/Free Full Text] - Cooper JA, Miller GJ, Bauer KA, Morrissey JH, Meade TW, Howarth DJ, Barzegar S, Mitchell JP, Rosenberg RD. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation. 2000; 102: 2816–2822.
[Abstract/Free Full Text] - Ardlie KG, Lunetta KL, Seielstad M. Testing for population stratification and association in four case-control studies. Am J Hum Genet. 2002; 71: 304–311.[CrossRef][Medline] [Order article via Infotrieve]
- Newton-Cheh C, O’Donnell CJ. Sex differences and genetic associations with myocardial infarction. JAMA. 2004; 291: 3008–3010.
[Free Full Text] - Koch W, Hoppmann P, Pfeufer A, Mueller JC, Schomig A, Kastrati A. No replication of association between estrogen receptor alpha gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent. Circulation. 2005; 112: 2138–2142.
[Abstract/Free Full Text] - Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science. 2005; 308: 1583–1587.
[Abstract/Free Full Text] - Mendelsohn ME, Rosano GM. Hormonal regulation of normal vascular tone in males. Circ Res. 2003; 93: 1142–1145.
[Free Full Text] - Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA, Bleecker ER. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002; 105: 1879–1882.
[Abstract/Free Full Text] - Koivu TA, Fan YM, Mattila KM, Dastidar P, Jokela H, Nikkari ST, Kunnas T, Punnonen R, Lehtimaki T. The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women. Maturitas. 2003; 44: 29–38.[CrossRef][Medline] [Order article via Infotrieve]
- Kunnas TA, Lehtimaki T, Karhunen PJ, Laaksonen R, Janatuinen T, Vesalainen R, Nuutila P, Knuuti J, Nikkari ST. Estrogen receptor genotype modulates myocardial perfusion in young men. J Mol Med. 2004; 82: 821–825.[CrossRef][Medline] [Order article via Infotrieve]
- Kunnas TA, Laippala P, Penttila A, Lehtimaki T, Karhunen PJ. Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study. BMJ. 2000; 321: 273–274.
[Free Full Text] - Pollak A, Rokach A, Blumenfeld A, Rosen LJ, Resnik L, Dresner Pollak R. Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease. Eur Heart J. 2004; 25: 240–245.
[Abstract/Free Full Text] - 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.
[Abstract/Free Full Text] - Ioannidis JPA, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JBJ, Mosekilde L, Scollen S, Albagha OME, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JPTM, Mavilia C, Masi L, McGuigan FEA, Nogues X, Pols HAP, Reid DM, Schuit SCE, Sherlock RE, Uitterlinden AG. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA. 2004; 292: 2105–2144.
[Abstract/Free Full Text] - American Heart Association. Heart Disease and Stroke Statistics—2004 Update. Dallas, Tex: American Heart Association; 2003.
This article has been cited by other articles:
 |
|
 |
|
  M. J. Bos, S. C.E. Schuit, P. J. Koudstaal, A. Hofman, A. G. Uitterlinden, and M. M.B. Breteler Variation in the Estrogen Receptor {alpha} Gene and Risk of Stroke: The Rotterdam Study Stroke, April 1, 2008; 39(4): 1324 - 1326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Douglas, M. Natalia Cruz, L. Poston, J.-A. Gustafsson, and K. Kublickiene Functional characterization and sex differences in small mesenteric arteries of the estrogen receptor- knockout mouse Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R112 - R120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Rexrode, P. M. Ridker, H. H. Hegener, J. E. Buring, J. E. Manson, and R. Y.L. Zee Polymorphisms and Haplotypes of the Estrogen Receptor-{beta} Gene (ESR2) and Cardiovascular Disease in Men and Women Clin. Chem., October 1, 2007; 53(10): 1749 - 1756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kato, B. Lindholm, J. Axelsson, R. A. Qureshi, P. Barany, O. Heimburger, J.-A. Gustafsson, P. Stenvinkel, and L. Nordfors Association between oestrogen receptor {alpha} gene polymorphism and mortality in female end-stage renal disease patients Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2571 - 2577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sun, C. Yan, A. Jacobson, H. Jiang, M. A. Carroll, and A. Huang Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ER{alpha} knockout mice: role of aromatase Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1239 - R1246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Murphy and C. Steenbergen Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury Cardiovasc Res, August 1, 2007; 75(3): 478 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Alevizaki, K Saltiki, A Cimponeriu, I Kanakakis, N Xita, C C Alevizaki, I Georgiou, and H-L Sarika Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor {alpha} polymorphic variants Eur. J. Endocrinol., April 1, 2007; 156(4): 489 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Deschepper and B. Llamas Hypertensive Cardiac Remodeling in Males and Females: From the Bench to the Bedside Hypertension, March 1, 2007; 49(3): 401 - 407. [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Kjaergaard, C. Ellervik, A. Tybjaerg-Hansen, C. K. Axelsson, M.-L. M. Gronholdt, P. Grande, G. B. Jensen, and B. G. Nordestgaard Estrogen Receptor {alpha} Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture: Cross-Sectional, Cohort, and Case-Control Studies and a Meta-Analysis Circulation, February 20, 2007; 115(7): 861 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. KLOUCHE Estrogens in Human Vascular Diseases Ann. N.Y. Acad. Sci., November 1, 2006; 1089(1): 431 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Pepine, W. W. Nichols, and D. F. Pauly Estrogen and Different Aspects of Vascular Disease in Women and Men Circ. Res., September 1, 2006; 99(5): 459 - 461. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Arnlov, M. J. Pencina, S. Amin, B.-H. Nam, E. J. Benjamin, J. M. Murabito, T. J. Wang, P. E. Knapp, R. B. D'Agostino Sr., S. Bhasin, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med, August 1, 2006; 145(3): 176 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Shearman Oestrogen receptor genetics: a needle that cuts through many haystacks? Eur. Heart J., July 1, 2006; 27(13): 1519 - 1520. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||