Estrogen Receptor α Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture
Cross-Sectional, Cohort, and Case–Control Studies and a Meta-Analysis
Background— We hypothesized that the estrogen receptor α (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture.
Methods and Results— We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case–control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12 190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21).
Conclusions— ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.
Received January 20, 2006; accepted October 24, 2006.
Estrogens are important hormones that exert their actions via estrogen receptors that influence multiple organ systems in both men and women, including cardiovascular, reproductive, and skeletal systems.1 Therefore, genetic variation in estrogen receptors could influence the risk of cardiovascular disease (CVD), cancer of reproductive organs, and osteoporotic bone fracture.
Clinical Perspective p 871
The C allele but not the T allele of the ESR1 IVS1-397T/C polymorphism produces a binding site for the myb family of transcription factors.2 Because B-myb expression is itself responsive to estrogen activation, the presence of the C allele might amplify ESR1 transcription and thus estrogen actions. Postmenopausal women with ESR1 IVS1-397T/C CC versus TT genotype undergoing hormone replacement therapy (HRT) had an augmented response of high-density lipoprotein (HDL) cholesterol levels3 and greater reductions in E-selectin,2 both of which could influence risk of disease in estrogen-responsive organ systems. In addition, there have already been several studies of the ESR1 IVS1-397T/C polymorphism in relation to CVD,4–16 breast cancer,17–24 endometrial cancer,25,26 prostate cancer,27–31 and hip fracture,32,33 although the results have been conflicting. It is therefore biologically plausible that the ESR1 IVS1-397T/C polymorphism may modify the effect of endogenous estrogen on risk of CVD, cancer of reproductive organs, and osteoporotic fractures like hip fracture.
In cross-sectional studies, we tested the hypothesis that genotype affects HDL cholesterol response to HRT. Furthermore, in cohort and case–control studies, we tested the hypothesis that the ESR1 IVS1-397 T/C polymorphism affects risk of CVD, cancer of reproductive organs, and hip fracture. Finally, we updated a recent meta-analysis11 on the effect of this genotype on risk of myocardial infarction (MI).
The studies were approved by institutional review boards and the Danish ethics committee (No. 100.2039/91, Copenhagen and Frederiksberg Committee, and KA 99039 and KA 02152, Copenhagen County Committee). Written informed consent was obtained from participants.
Cross-Sectional and Cohort Studies
The Copenhagen City Heart Study is a prospective study of the Danish general population. Participants were examined in 1976–1978, 1981–1983, and 1991–1994; 4127 men and 5117 women were genotyped for the present study (see the Methods section in the online-only Data Supplement).
CVD included ischemic heart disease (IHD) with the subclasses of MI (fatal and nonfatal) and angina pectoris, ischemic cerebrovascular disease (ICVD) with the subclasses of ischemic stroke and ICVD other than stroke, and venous thromboembolism (VTE) with the subclasses of deep vein thrombosis and pulmonary embolism. Cancer of reproductive organs included cancers of breasts, ovaries, and uterus separately and combined as “female cancer” in women and prostate cancer in men.
Diagnoses of CVD, cancers, and hip fracture were obtained from the Danish National Hospital Discharge Registry, the Danish National Registry of Causes of Death, and the Danish Cancer Registry (see Data Supplement Methods). We followed up all individuals from entry into the study until occurrence of the relevant event, death, or the end of the year 2000 (for CVD and hip fracture) or 2002 (for cancers), whichever came first. The follow-up was 100%. Persons with end points at baseline or before the beginning of follow-up were excluded from the relevant study.
We also recruited 2495 patients with IHD referred during 1991–2004 to Rigshospitalet, Copenhagen University Hospital, for coronary angiography, 856 patients with ICVD referred during 1994–2004 to Rigshospitalet for ultrasonography of the carotid arteries, and 1256 female patients with invasive breast cancer referred during 2001–2004 to the Department of Breast Surgery, Herlev University Hospital (see Data Supplement Methods).
All participants were genotyped for the ESR1 IVS1-397 T/C polymorphism (identical to IVS1-401 T/C, PvuII restriction fragment length polymorphism, and ESR1 c.454 to 397 T>C) by a TaqMan assay (Applied Biosystems, Foster City, Calif). Primer and probe sequences were optimized by using the single-nucleotide polymorphism assay-by-design service of Applied Biosystems. Reactions were performed with the TaqMan Prism 7900HT 384-well format. Positive and negative controls were included in genotyping assays. We retested 255 plus 311 randomly selected persons using an AluI restriction enzyme assay and a PvuII restriction enzyme assay, as well as sequencing (see Data Supplement Table I). The results agreed 100% among the 4 methods. No other single nucleotide polymorphisms were detected that could interfere with the TaqMan method (see Data Supplement Methods, Figure 2, and Table II).
Body mass index was calculated as weight in kilograms divided by height in meters squared. Diabetes mellitus was defined as self-reported disease, current use of insulin or other medication for treatment of diabetes, or a nonfasting plasma glucose >11.0 mmol/L. Hypertension was defined as use of antihypertensive medication, systolic blood pressure ≥140 mm Hg, or diastolic blood pressure ≥90 mm Hg. Smokers were active smokers.
A 2-sided value of P<0.05 was considered statistically significant. We used the statistical software package Stata/SE 8.0 (Stata Corp, College Station, Tex). For power calculations, NCSS-PASS was used. With the assumption of 2-sided values of P<0.05 and the observed number of events/nonevents or cases/noncases, we calculated the hazard ratio/odds ratio that could be detected in our studies at 90% power. All analyses were stratified by gender. Pearson’s χ2 test was used for categorical variables, the Mann-Whitney U test for continuous variables, and general linear models for combinations. We tested differences in cumulative incidence of disease between genotypes using the log-rank test. Left truncation (see Data Supplement Methods) was used with age as the time scale in a Cox proportional-hazards model to estimate hazard ratios using time-dependent covariates. Thus, differences in age are automatically adjusted for. We detected no violations of the proportional-hazards assumption over time for any covariate, as tested with Schoenfeld residuals. In age- and gender-matched case–control designs, conditional logistic regression models were used to estimate odds ratios for CVD and breast cancer. In multifactorially adjusted models, results were similar whether continuous covariates were transformed into tertiles or were continuous. Interactions between ESR1 genotypes and continuous and categorical covariates were tested for statistical significance by using the likelihood ratio test to compare the model with or without the 2-factor interaction term. We used Bonferroni correction for multiple comparisons. For meta-analysis, see the Data Supplement Methods.
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Characteristics of participants (Data Supplement Tables III and IV) did not differ by ESR1 IVS1-397T/C genotype in the general population (data not shown). ESR1 IVS1-397T/C CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Genotype frequencies were similar for women and men and did not differ from those predicted by Hardy-Weinberg equilibrium (χ2 test, P>0.70).
In 2802 postmenopausal women in the general population, HRT raised HDL cholesterol levels independently of ESR1 IVS1-397T/C genotype in both the 1981–1983 and 1991–1994 examinations (tests of interaction, P=0.82 and P=0.42) (Figure 1).
During a median 23 to 25 years of follow-up, 1666 individuals developed CVD, 1137 developed IHD, 510 developed ICVD, and 285 developed VTE (Tables 1 and 2⇓). Furthermore, 380 women developed female cancer (breast, ovarian, and uterine cancers combined), 116 men developed prostate cancer, and 273 individuals had a hip fracture.
Cumulative incidences of CVD, IHD, ICVD, VTE, female cancer, prostate cancer, and hip fracture were similar for all genotypes in both genders (all log-rank tests, P>0.05; data not shown). Hazard ratios for CVD, IHD, ICVD, VTE, female cancer, prostate cancer, and hip fracture in CT and TT genotypes versus the CC genotype did not differ from 1.0 when adjusted for age or after multifactorial adjustment in either gender (Tables 1 and 2⇑). In women, we had 90% statistical power to detect hazard ratios in TT versus CC genotypes of 1.3 for CVD, 1.4 for IHD, 1.6 for ICVD, 1.8 for VTE, 1.5 for female cancer, and 1.7 for hip fracture. In men (with prostate cancer instead of female cancer), the equivalent values were 1.3, 1.3, 1.5, 1.8, 1.8, and 1.8.
Subanalyses of end points showed no difference in cumulative incidences of MI (total, fatal, and nonfatal), angina pectoris, ischemic stroke, ICVD other than stroke, deep vein thrombosis, pulmonary embolism, breast cancer, ovarian cancer, and uterine cancer between ESR1 IVS1-397 genotypes (all log-rank tests, P>0.05; data not shown); we observed 562 (379 fatal, 183 nonfatal), 576, 397, 113, 192, 128, 257, 43, and 91 of these end points, respectively, during the 23 to 25 years of follow-up. Hazard ratios for MI, angina pectoris, ischemic stroke, ICVD other than stroke, deep vein thrombosis, pulmonary embolism, breast cancer, ovarian cancer, and uterine cancer in CT and TT genotypes versus CC genotype did not differ from 1.0 when adjusted for age or after multifactorial adjustment (Tables 1 and 2⇑).
We searched extensively for statistical evidence of bivariate multiplicative interaction between genotypes and the covariates listed in Data Supplement Table V, each of which could affect risk of CVD, cancer of reproductive organs, and/or hip fracture; 2 of 52 tests of interaction had a value of P<0.05, but after correction for multiple comparison, these were no longer significant. Furthermore, when we explored these potential interactions by stratification (Data Supplement Table VI), the observed irregular patterns were not statistically significant and thus suggested chance findings rather than plausible interactions. Figure 2 also shows that there is no plausible consistent interaction between genotype and age on cardiovascular end points when baseline age is categorized in 2 or 3 equally sized groups; however, decreased risk of MI in CT and TT versus CC 20- to 50-year-old men cannot be excluded (Figure 3).
Odds ratios for IHD and ICVD in CT and TT genotypes versus the CC genotype did not differ from 1.0 when adjusted for age or after multifactorial adjustment in either gender (Table 3). Subanalyses of end points showed that odds ratios for MI, angina pectoris, ischemic stroke, and ICVD other than stroke in CT and TT genotypes versus the CC genotype did not differ from 1.0 regardless of adjustment.
Age-matched odds ratio for breast cancer in women with the TT versus CC genotype was 1.2 (95% CI, 1.0 to 1.5) (Table 3). After additional multifactorial adjustment, the equivalent odds ratio was 1.4 (95% CI, 1.1 to 1.7). We had 90% statistical power to detect an odds ratio ≥1.3 in TT versus CC genotypes.
Testing for bivariate multiplicative interaction between genotypes and other covariates (Data Supplement Table VII) resulted in 2 statistically significant tests out of 49 tests. After stratification (Data Supplement Table VI), only 1 test remained statistically significant but did not appear biologically plausible. Furthermore, after correction for multiple comparisons, the interaction was only borderline significant and thus most likely represents a chance finding.
When 6 previous studies8–11 and the present 2 studies were combined (4799 cases and 12 190 controls), the CC genotype versus CT and TT genotypes combined had an odds ratio for fatal and nonfatal MI of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21) (Figure 4) (see Data Supplement Results).
A strength of our study is that it includes a prospective study of the general population and is the largest and statistically most powerful cohort study to date addressing whether risk of disease is associated with ESR1 IVS1-397T/C genotype. We studied a homogenous population with men and women separately in which 99% of the participants were whites of Danish descent. Another strength is that we retested main hypotheses in large, independent case–control studies.
Important new findings include that our study rebuts the current hypothesis that the ESR1 IVS1-397T/C polymorphism is associated with risk of MI and other CVDs in both men and women but that this polymorphism possibly is associated with a modest increase in risk of breast cancer.
In contrast to a previous study,3 we were not able to demonstrate augmented response of HDL cholesterol to HRT by ESR1 genotype. The former study examined 309 women with coronary artery disease randomized between HRT and placebo, whereas we studied 2802 women from the general population. Although treatment was not assigned randomly to postmenopausal women in our study, genotype is distributed randomly regardless of treatment because of Mendelian randomization.34
Despite previous evidence,5–9,11–16 the ESR1 IVS1-397T/C polymorphism was not associated with risk of CVD, overall or in any subgroup, in our cohort study of 9244 participants followed up for 23 to 25 years or in our case–control studies of 2495 IHD cases versus 4447 controls and of 856 ICVD cases versus 2335 controls.
In the Framingham Offspring Study of 1739 participants followed up for 27 years, the CC versus TT genotype was associated with an odds ratio for MI of 2.7 (95% CI, 1.4 to 5.1) in men.8 This finding confirmed a previously reported association between coronary artery disease and the CC genotype in a Finnish autopsy study of 262 men7 and in 295 Japanese, predominantly male, patients with familial hypercholesterolemia.6 In contrast, in the Rotterdam Study of 6408 participants followed up for 7 years, the TT versus CC genotype was associated with a relative risk for MI of 2.5 (95% CI, 1.2 to 5.0) in women but not in men.9 Finally, a Japanese case–control study of 87 cases with MI or angina pectoris and 94 controls4 and a recent German study of 3657 patients with MI versus 1211 controls10 did not observe an association between IVS1-397T/C genotype and risk of MI.
The results of the Framingham Offspring Study and Rotterdam Study thus seemingly contradict each other; certainly, the results of neither study are compatible with ours. In subanalyses, our data suggested increased risk of MI in CC versus CT/TT younger men, whereas the Framingham study showed increased risk in older men (see Data Supplement Discussion). Nevertheless, this polymorphism could have a very different effect in the 2 genders, effects that even could differ between different contexts in different countries. There is always a high risk of false-positive associations because of chance findings, and the results of the ESR1 IVS1-397T/C single-nucleotide polymorphism in the Framingham and Rotterdam studies could be examples of such (like our association with breast cancer). In accordance with this idea, in men, we had 90% power to exclude a hazard ratio of ≥1.4 for MI in the cohort study and an odds ratio of ≥1.5 for MI in the case–control study, whereas the Framingham Offspring Study detected an odds ratio of 2.7. Likewise, in women, we had 90% power to exclude a hazard ratio of ≥1.6 for MI in our cohort study and an odds ratio of ≥1.8 for MI in our case–control study, whereas the Rotterdam Study detected a relative risk of 2.5 for MI. Furthermore, a large German case–control study did not observe an association between IVS1-397T/C genotype and risk of MI in either gender; this study had 90% power to exclude an odds ratio of ≥1.4 in men and ≥1.5 in women.
A recent meta-analysis11 of 5 studies in men only, including 731 cases and 6111 controls, showed an odds ratio for nonfatal MI in CC versus CT/TT individuals of 1.44 (95% CI, 1.17 to 1.76). When we updated this meta-analysis with a recent publication10 and the 2 present studies, adding 4021 cases and 6079 controls, the equivalent odds ratios were 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21) for fatal and nonfatal MI, respectively. The recent meta-analysis11 also suggested increased MI risk by genotype in older versus younger men. Our 2 studies with more statistical power were not able to confirm this suggestion.
Cancer of Reproductive Organs
In our case–control study on breast cancer with 1256 cases versus 2489 controls, women with TT versus CC genotypes had a 40% increased risk of breast cancer. At first look, our case–control study would seem to contradict our cohort study; therefore, this observation likely could represent a chance finding. However, in the case–control study, we had 90% statistical power to detect an odds ratio for breast cancer of ≥1.3 in TT versus CC genotypes, whereas in the cohort study, we had power to exclude an equivalent hazard ratio of only ≥1.6. Therefore, we cannot exclude that women with the TT genotype may have a modest increase in risk of breast cancer.
Previous smaller studies18–21,23 and a recent large cohort study24 (4248 women followed up for 12.4 years; 252 events) on the association between the ESR1 IVS1-397T/C polymorphism of the ESR1 and risk of breast cancer showed no association, whereas a Chinese case–control study of 1069 cases and 1166 controls, in accordance with our results, showed an increase in risk of breast cancer with age-adjusted odds ratios for IVS1-397T/C genotypes TT versus CC of 1.4 (95% CI, 1.1 to 1.8).22 Furthermore, a combined odds ratio for 5 of the previous studies17–20,22 was 1.23 (95% CI, 1.08 to 1.43) on risk of breast cancer for TT versus CC genotype of the ESR1 IVS1-397T/C polymorphism.17
Our observation of no association between ESR1 genotype and risk of hip fracture is in accordance with a meta-analysis of 18 917 individuals from 8 European centers.33 However, we had only 90% power to exclude a hazard ratio for hip fracture of ≥1.7 in women and ≥1.8 in men.
Under the common disease/common variant model, effect sizes for single-nucleotide polymorphisms could be as small as an odds ratio of ≈1.2. Because the hazard ratio/odds ratio for 90% power for several of our outcomes was considerably larger than 1.2, our data do not preclude smaller effects that nevertheless could be important because of the prevalence of the genetic variant in question.
Some of our end points, including the subgroups of ICVD, VTE, and female cancer, along with hip fracture and prostate cancer, appear to be too small to draw meaningful conclusions. As with many prospective studies, small event rates for these end points are a severe limitation of the cohort study presented here.
We thank Mette Refstrup, Nina Dahl Kjersgaard, and Birgit Hertz for technical assistance.
Sources of Funding
This work was supported by the Danish Heart Foundation, Danish Medical Research Council, and Chief Physician Johan Boserup and Lise Boserup’s Fund, as well as by research funds from Rigshospitalet, Copenhagen University Hospital, Herlev University Hospital, and Copenhagen County.
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This study rebuts the current hypotheses that the estrogen receptor α IVS1-397T/C polymorphism augments the response of high-density lipoprotein cholesterol to hormone replacement therapy in postmenopausal women and is associated with an increased risk of myocardial infarction and other cardiovascular diseases in both men and women. Additionally, this polymorphism is potentially associated with a modest increase in risk of breast cancer. The major strength of this study is that it is a prospective study of the general population and is the largest and statistically most powerful cohort study to date addressing whether risk of disease is associated with this genotype. We studied a homogeneous population with men and women separately; 99% of the participants were whites of Danish descent. Another strength is that we retested main hypotheses in large, independent case–control studies. Taken together, our data do not support that the estrogen receptor α IVS1-397T/C polymorphism should influence diagnosis, prevention, or treatment of cardiovascular diseases.
The online-only Data Supplement, consisting of expanded Methods, figures, and tables, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.615567/DC1.