© 1997 American Heart Association, Inc.
Articles |
Genotype Distribution of Estrogen Receptor Polymorphisms in Men and Postmenopausal Women From Healthy and Coronary Populations and Its Relation to Serum Lipid Levels
From the Department of Medicine, School of Medicine, Keio University, Tokyo, Japan (Y.M., M.M., T.Z., Y.I.); the Second Department of Internal Medicine, Kyorin University, Tokyo, Japan (K.K., N.A., H.Y., K.I.); and the Health Center, Sakura Bank, Tokyo, Japan (G.W.).
Correspondence to Mitsuru Murata, MD, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
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Abstract |
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Abstract The cardiovascular protective effects of estrogen are known to be mediated by its beneficial effects on lipid metabolism and its direct actions on the vessel wall. The latter can be mediated by a specific receptor for estrogen present on smooth muscle cells and endothelial cells. The gene for the receptor (the classic estrogen receptor [ER]) has three known polymorphisms, Pvu II, Xba I, and B-variant polymorphisms, which are reportedly associated with receptor expression and altered receptor function and with some disorders including breast cancer, hypertension, and spontaneous abortion. However, the significance of genetic variations of the ER in vascular diseases has not been reported. We have examined the association between coronary artery disease (CAD) and the three polymorphisms in ER. Genotypes (P1/P2, X1/X2, and B-wild type/B-variant type) were determined in 87 men and postmenopausal women with myocardial infarction or angina pectoris whose lesions were confirmed by coronary angiography, as well as from 94 control individuals from the general population with no coronary heart disease and normal resting ECG. For B-variant polymorphism, all individuals examined had B-wild type, which contrasts with the reported allele frequency for B-variant type (0.1) in the white population. Genotype distributions and allele frequencies of Pvu II or Xba I polymorphisms were not significantly different between control subjects and patients (P>.05 for Pvu II or Xba I genotypes; P>.05 for Pvu II or Xba I allele frequencies). When the allele frequencies were analyzed separately by sex, there was still no statistically significant difference for both polymorphisms (P>.05 for men; P>.05 for women). No association was found between the polymorphisms and the angiographic severity of CAD. Total cholesterol, triglyceride, or HDL-cholesterol levels were not significantly different among ER genotypes. These findings suggest that the three polymorphisms in ER are not associated with the prevalence and severity of CAD and that the polymorphisms are unrelated to the serum lipid levels in control subjects and patients.
Key Words: estrogen receptor • coronary artery disease • polymorphisms • genetics • risk factors
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Introduction |
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Epidemiologic and experimental evidence has now accumulated to indicate the cardiovascular protective roles of estrogens.1–4 The atheroprotective effects of estrogens are mediated by at least two basic mechanisms: first, they affect lipoprotein metabolism; second, they have direct effects on the vessel wall. The endogenous and exogenous estrogens decrease LDL-cholesterol and increase HDL-cholesterol levels.4 It is believed that estrogen leads to an increase in the messenger RNA for the LDL receptor.5 Estrogens have also direct effects on vascular smooth muscle cells and vascular endothelial cells. They inhibit cell proliferation6 and induce vasodilation by regulating membrane ionic permeability and by modulating endothelium-derived relaxing factors.7,8
Vascular smooth muscle cells as well as vascular endothelial cells contain a specific receptor with a high affinity for estrogen.9–12 It is still not fully understood whether the effects of estrogen on cardiovascular systems are totally dependent on the classical ER. Indeed, the presence of other mechanisms independent of the ER have also been reported.7,13,14 It is possible, however, that the alterations in ER expression and its function might affect the atheroprotective roles of estrogens. A recent study on postmortem coronary artery specimens has demonstrated that there is an association between the presence of ER expression and the absence of coronary atherosclerosis in premenopausal women.9
Three polymorphisms in the gene encoding ER have been reported in the genomic DNA extracted from human breast tumors and normal human peripheral blood leukocytes.15–22 The first polymorphism, a Pvu II polymorphism that is caused by a T/C transition (P2/P1) in intron 1, is located approximately 0.4 kb upstream of exon 2.18 An association between the P2 allele (allele with T nucleotide) and the more frequent ER expression in breast cancer was reported.17 It is speculated that the Pvu II polymorphism affects the splicing of ER mRNA, resulting in the alteration of protein expression.17 Another report has suggested a significant association between the Pvu II genotypes and the onset age in breast cancer patients; those homozygous for the P2 allele were younger than those having the P1 allele.19 A recent study of healthy, postmenopausal Japanese women has demonstrated that individuals with a P1/P1 genotype tend to have a low z score of bone mineral density.20 The second polymorphism is a Xba I polymorphism, which is located approximately 50 bp apart from the Pvu II polymorphism site. It has been reported that the X2 allele (Xba I restriction site [+]) was more frequently found in genomic DNA from breast cancer patients than from control subjects.21 A high degree of linkage disequilibrium between Xba I and Pvu II polymorphisms has been reported,20,22 P2 being linked to X2. The third polymorphism is the B-variant polymorphism, caused by a G/C transversion (B-wild type/B-variant type) at nucleotide number 493 in exon 1 (numbers according to Green et al23). This results in a silent mutation at residue 87 of the ER, which is located within a transcriptional activation domain of the receptor.15,24,25 The allele frequencies for wild type and variant type in the general white population are 0.9 and 0.1, respectively,22 although the allele frequencies in the Japanese population have not been reported to date. The relationships of B-variant polymorphism to spontaneous abortion25,26 and hypertension27 have been reported. It is of interest that ERs with B-variant type had decreased binding affinity to estrogen,24 although the mechanisms involved are not clearly understood. It is thus speculated that estrogen may have a lesser benefit on the cardiovascular system in individuals having B-variant type ERs and that the presence of B-variant type might be a genetic risk factor for CAD.
These observations prompted us to test the hypothesis that genetic variations in ERs could be a risk factor for cardiovascular disorders. Although the three polymorphisms in the ER may determine some characteristics of human breast tumors and may be associated with bone metabolism and abortion, relationships between these polymorphisms and CAD have not been reported to date. Therefore, we sought to assess the associations of the three ER polymorphisms with the prevalence and severity of CAD. We have evaluated the genotypes and allele frequencies in male patients and postmenopausal female patients with angiographically proven CAD in comparison with control subjects. We also investigated the relationships between these polymorphisms and serum lipid levels.
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Methods |
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Patients and Control Subjects
Eighty-seven genetically unrelated Japanese patients (men, 65; women, 22) with either MI (men, 51; women, 17) or angina pectoris (men, 14; women, 5), recruited at Kyorin University Hospital, were analyzed (Table 1
). Their ages
were 38 to 79 years (58.2±9.4, mean±SD) and 51 to 75 years
(64.7±6.2) for men and women, respectively. Diagnosis of MI was based
on clinical symptoms, appropriate new onset of electrocardiographic
changes, and elevated serum creatine phosphokinase levels. Only
patients whose diagnosis of MI was made at this hospital were entered
into this study. All patients with MI except 10 were evaluated by
coronary angiography. Diagnosis of angina pectoris was made
according to clinical symptoms and EKG findings, and only those
patients whose coronary lesions were confirmed by
coronary angiography were eligible for this study. An affected
vessel was defined as having >50% reduction of lumen size (
75%
stenosis on American Heart Association classification). For
patients with MI, ages at their first events were recorded, whereas
for patients with angina pectoris, ages at which coronary
angiography was performed were recorded. Ninety-four control
subjects (men, 75; women, 19) were selected from the healthy,
genetically unrelated Japanese population, who had no history of angina
or other heart diseases and had a normal resting EKG. Their ages ranged
from 36 to 59 years (49.0±5.5, mean±SD) and 50 to 81 years
(61.8±8.3) for men and women, respectively. Patients and control
subjects never had a sex-hormone-dependent disease. No individual in
this study population was receiving or had previously received hormone
replacement therapy. All women were postmenopausal. Clinical data
including body-mass index, smoking history, blood pressure, serum total
cholesterol level, triglyceride level,
HDL-cholesterol level, and diabetes status were collected
from medical records of patients.
Hypercholesterolemia was defined as a total
cholesterol level >220 mg/dL at
presentation or a pretreatment cholesterol
level >220 mg/dL.
Hypertriglyceridemia was defined as a
triglyceride level >150 mg/dL at
presentation or a pretreatment triglyceride
level >150 g/dL. These data for control subjects were collected
from regular check-up sheets.
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Documentation of CAD Severity
To determine the severity of CAD, we used two systems:
Gensini's coronary artery scoring
method28 and affected vessel numbers. In the
former scoring system, the geometrically increasing severity of
lesions, the cumulative effects of multiple obstructions, the
significance of their locations, the modifying influence of the
collaterals, and the size and quality of the distal vessels were taken
into consideration. In the latter system, the severity of CAD was
expressed simply by affected vessel numbers, classifying numbers
between one and three. The lesion at left main coronary artery
was regarded as two-vessel disease.
Preparation of Genomic DNA and Determination of ER
Genotypes
Blood was obtained from peripheral veins of patients
and control subjects after informed consent. Genomic DNA was isolated
from leukocytes as described.29 Three
polymorphisms in the ER gene were analyzed by polymerase
chain reaction-restriction fragment length polymorphism methods.
For the first (Pvu II) and the second (Xba I)
polymorphisms, a 1.3-kb DNA fragment of the ER gene that contains
the two polymorphic sites in intron 1 was amplified by polymerase
chain reaction as described with some
modifications.18 For the third polymorphism
(B-variant polymorphism), a 195-bp DNA fragment in exon 1 was
amplified as described.21 Amplified DNA was
digested with Pvu II or Xba I (Takara Shuzo) at
37°C for 3 hours, or with BstU1 (New England BioLabs) at
60°C for 3 hours, to determine genotypes.
Statistics
To examine whether the P1/P1 genotype would be a genetic
risk factor for CAD, with the use of the 
2
test, a sample size of 79 was estimated by the formula
described30 (two-sided 
error=0.05,
power=0.8), when the expected prevalence of P1/P1genotype in
our patients would be 40% based on the frequency previously reported
in healthy Japanese women.20 Student's t test
was used to compare ages and body mass index, and ANOVA was used for
comparison of serum lipid levels between control subjects and patients.
Statistical analyses of frequency counts were performed
with the use of the 2 test or Fisher's exact
test for small samples. The Mantel extension
method31 was used for the purpose of age
adjustment in the study population to compare the distribution of three
genotypes (P1/P1, P1/P2, and P2/P2, or X1/X1, X1/X2, and X2/X2)
between control subjects and patients. P<.05 was considered
significant. The odds ratio was used as a measure of the ratio of P1/P1
to P1/P2+P2/P2 or the ratio of X1/X1+X1/X2 to X2/X2. Variability in
sampling associated with the estimated odds ratio was assessed by
two-sided 95% CI. Odds ratio (95% CI) >1 was considered to be
significant. The linkage disequilibrium (
) was estimated as
described.32,33
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Results |
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The mean age was higher in the male patients (58.2±9.4 years) than in the male control subjects (49.0±5.5 years; mean±SD, Table 1
).
The mean ages in women were not significantly different between control
subjects (61.8±8.3 years) and patients (64.7±6.2 years). There were
65 (74.7%) and 75 (79.8%) men in the patient and control groups,
respectively. The patient group had a higher prevalence of selected
coronary risk factors (smoking, hypertension, diabetes
mellitus, and hypertriglyceridemia for men;
smoking and hypertension for women) than the control group. In contrast with the previous report on whites,22 the genotype with B-variant polymorphism was not detected in either the control group or the patient group, ie, all individuals tested in this study were homozygous for BstU1(-) (not shown in tables).
Genotypes and allele frequencies of Pvu II
or Xba I polymorphisms in the control subjects and the
patients are shown in Table 2. For
Pvu II polymorphism, all subjects enrolled (94 control
subjects and 87 patients) were analyzed, whereas only 89
control subjects and 75 patients were available for the
analysis of Xba I. The genotype
distributions and allele frequencies of the two polymorphisms
were compared by 2 test with df=2
and df=1, respectively (by a 2x3 contingency table for
genotypes or a 2x2 contingency table for allele
frequencies). Genotype distributions and allele frequencies
of Pvu II and Xba I polymorphisms were not
significantly different between control subjects and patients
(P>.05 for Pvu II or Xba I
genotypes; P>.05 for Pvu II or
Xba I allele frequencies). The odds ratios for P1/P1 to
P1/P2+P2/P2 was 1.004 (95% CI, 0.43 to 2.35) and for X1/X1+X1/X2 to
X2/X2 was 0.974 (95% CI, 0.51 to 1.86). Neither of these was
statistically significant. For both polymorphisms, no statistically
significant difference in allele frequencies was found even when
men and women were analyzed separately (P>.05,
women; P>.05, men). In addition, genotype
distributions were not significantly different between male control
subjects and patients or between female control subjects and patients
after adjustment for age (data not shown). The mean ages of onset of
CAD were not significantly different between genotypes in the
patients (P>.05, Table 2). Also, the mean ages of our
control subjects were not different between three genotypes of
Pvu II or between three genotypes of Xba
I polymorphisms (P>.05, data not shown in Table 2).
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Relationships between Pvu II or Xba I
genotype and disease status among patients are shown in Table 3. The frequency of P1 allele was
40.4% for patients with MI whereas it was 47.4% for angina patients,
showing no significant difference (P>.05). Patients with
multi-vessel (two or more) disease tended to have higher frequency for
P2 allele; 51.4% for single-vessel disease whereas 63.8% for
multi-vessel disease, although the difference was not statistically
significant (P>.05). Frequencies of P2 allele were
57.6% for G-score 
40 and 58.1% for G-score
>40, showing no significant difference (P>.05). The
frequency of X2 allele was 83.3% for patients with MI, whereas it
was 80.0% for angina patients (P>.05). Patients with
multi-vessel (two or more) disease tended to have a higher frequency
for the X2 allele: 78.3% for single-vessel disease versus 84.7%
for multi-vessel disease, although the difference did not reach a
statistical significance (P>.05). Frequencies of X2
allele were 84.2% for G-score 40 and 78.6% for
G-score >40, showing no significant difference
(P>.05).
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Table 4 shows the relationships between
the mean serum lipid levels and Pvu II or Xba I
genotypes in control subjects and patients. In this table, only
those not taking any lipid-lowering drugs were included. Comparison of
available data for total cholesterol,
triglyceride, and HDL-cholesterol levels showed
that there is no statistically significant difference between the three
genotypes within the control group or within the patient group
as calculated by ANOVA.
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We also analyzed the linkage disequilibrium between
Pvu II polymorphism and Xba I
polymorphism (Table 5). As suggested
by a previous report on healthy postmenopausal Japanese
women,20 there is a linkage disequilibrium
between the two polymorphisms: 2=27.5,
P<.0001 (df=4), =0.53 for control subjects
and 2=27.3, P<.0001
(df=4), =0.54 for patients.
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Discussion |
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The cardiovascular protective effects of estrogen have been thought to be mediated by an indirect effect on lipoprotein metabolism. However, recent studies have revealed that all the beneficial effects of estrogen cannot be explained by alterations in serum lipid levels.34–36 Rosano et al35 and Williams et al36 have suggested that estrogens have direct effects on the coronary arteries, causing vasodilation without changing serum lipid levels. A recent study confirmed the expression of ER by human vascular smooth muscle cells and suggested an association between diminished receptor expression and the occurrence of premature coronary atherosclerosis.9 Several animal studies have suggested that the effects of 17ß-estradiol on cardiovascular systems37 or on vascular smooth muscle cells38 are mediated by ER.
Our study is the first to analyze the association between the genetic variation in ER and prevalence or severity of CAD. We have also analyzed the association with serum lipid levels. The genotype distributions of ER Pvu II and Xba I polymorphisms in our groups are similar to those reported in previous studies on breast cancer patients, testicular tumor patients, and healthy postmenopausal women.17–22 The P2 allele has previously been reported to be associated with increased ER expression in human breast tumors.17 Although the molecular basis of this association in breast tumors has not been fully elucidated, it was speculated that ER polymorphisms affected the proper splicing of ER messenger RNA or that the polymorphism was linked to some other polymorphism relevant for protein expression. However, the relationship between ER genotypes and the expression level or function of ER in vascular tissues has not been reported. Also, there have been no reports suggesting an association of the ER genotypes with cardiovascular diseases. We initially hypothesized that in subjects with the P1/P1 homozygote, ER expression on vascular cells would be low compared with subjects with P2/P2, and thus the P1/P1 subjects would benefit less from the cardiovascular protective effects of estrogens.
Recently, Kobayashi et al20 suggested that some variation of ER gene was associated with low bone mineral density in postmenopausal Japanese women. They found that the P1 allele was significantly associated with low bone mineral density, although conflicting results have also been reported.39 Since human osteoblastic cells and osteoclasts contain ER,40,41 genetic variation in the ER gene might affect bone metabolism. We also speculated that the genetic risk factors for age-dependent diseases such as CAD might change the age of disease onset in an allelic association study. Indeed, Parl et al19 have shown a significant association of early-onset breast cancer with the P2/P2 homozygote. In this study, we expected that individuals with the P1/P1 homozygote would have an early onset CAD. However, we have found no association between the age of CAD onset and either of the polymorphisms. The negative association between ER genotypes and CAD in our study could be explained, at least in part, by the existence of other estrogen-responsive mechanisms in cardiovascular cells such as a novel estrogen receptor ß-mediated mechanism.14
Interestingly, we have found no individual having ER with B-variant polymorphism among either control subjects and patients. This is the first report that analyzed the B-variant polymorphism in a Japanese population, showing a striking difference in the genotype distribution between Japanese and white populations. The allele frequency for B-variant in the latter population has been reported to be 0.1. A study on a Korean population also failed to identify any individual with B-variant type.39 In contrast, the genotype distributions for Pvu II and Xba I are comparable to those of whites, and there is a strong linkage between the two polymorphisms in our study population, which is the same observation as that previously reported 22.
Several lines of evidence have shown that women taking hormone replacement therapy have a lower incidence of CAD than those who are not taking it.42–44 It is also suggested, however, that hormone replacement therapy is associated with the risk of coagulopathy and with an increased risk for CAD, especially with the use of high doses of estrogen.42,45,46 The dose-dependent effects of estrogen administration on normal and damaged coronary arteries in vivo have not been completely defined. We have speculated that differences in the ER genotype among individuals might influence the occurrence and severity of CAD. Although the mutated receptors for estrogen with altered biologic function have not been reported, it is essential to elucidate the individual variation in the function of ER for deciding adequate doses of exogenous estrogen for the prevention and treatment of CAD.
In conclusion, we have reported a negative association between CAD and the genotype distribution of three polymorphisms on the ER gene. No relationship between ER genotype and serum lipid levels in patients and control subjects has been identified. This study, however, will contribute to a better understanding in the clinical use of estrogen therapy. Further studies will elucidate the role of genetic variations in the effect of estrogens on cardiovascular systems.
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Selected Abbreviations and Acronyms |
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Received February 14, 1997; accepted September 4, 1997.
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 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]
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W. Koch, P. Hoppmann, A. Pfeufer, J. C. Mueller, A. Schomig, and A. Kastrati 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, October 4, 2005; 112(14): 2138 - 2142. [Abstract] [Full Text] [PDF]
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 T. Yahata, J. Quan, N. Tamura, H. Nagata, T. Kurabayashi, and K. Tanaka Association between single nucleotide polymorphisms of estrogen receptor {alpha} gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women Hum. Reprod., July 1, 2005; 20(7): 1860 - 1866. [Abstract] [Full Text] [PDF]
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 R. K. Dubey, B. Imthurn, M. Barton, and E. K. Jackson Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen Cardiovasc Res, May 1, 2005; 66(2): 295 - 306. [Abstract] [Full Text] [PDF]
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 S. C. E. Schuit, H.-H. S. Oei, J. C. M. Witteman, C. H. Geurts van Kessel, J. B. J. van Meurs, R. L. Nijhuis, J. P. T. M. van Leeuwen, F. H. de Jong, M. C. Zillikens, A. Hofman, et al. Estrogen Receptor {alpha} Gene Polymorphisms and Risk of Myocardial Infarction JAMA, June 23, 2004; 291(24): 2969 - 2977. [Abstract] [Full Text] [PDF]
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A. Pollak, A. Rokach, A. Blumenfeld, L. J Rosen, L. Resnik, and R. Dresner Pollak Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease Eur. Heart J., February 1, 2004; 25(3): 240 - 245. [Abstract] [Full Text] [PDF]
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 V. Ferrero, F. Ribichini, G. Matullo, S. Guarrera, S. Carturan, A. Vado, C. Vassanelli, A. Piazza, E. Uslenghi, and W. Wijns Estrogen Receptor-{alpha} Polymorphisms and Angiographic Outcome After Coronary Artery Stenting Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2223 - 2228. [Abstract] [Full Text] [PDF]
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A. M. Shearman, L. A. Cupples, S. Demissie, I. Peter, C. H. Schmid, R. H. Karas, M. E. Mendelsohn, D. E. Housman, and D. Levy Association Between Estrogen Receptor {alpha} Gene Variation and Cardiovascular Disease JAMA, November 5, 2003; 290(17): 2263 - 2270. [Abstract] [Full Text] [PDF]
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H. Lu, T. Higashikata, A. Inazu, A. Nohara, W. Yu, M. Shimizu, and H. Mabuchi Association of Estrogen Receptor-{alpha} Gene Polymorphisms With Coronary Artery Disease in Patients With Familial Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 817 - 823. [Abstract] [Full Text] [PDF]
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 D. M. Herrington, T. D. Howard, G. A. Hawkins, D. M. Reboussin, J. Xu, S. L. Zheng, K. B. Brosnihan, D. A. Meyers, and E. R. Bleecker Estrogen-Receptor Polymorphisms and Effects of Estrogen Replacement on High-Density Lipoprotein Cholesterol in Women with Coronary Disease N. Engl. J. Med., March 28, 2002; 346(13): 967 - 974. [Abstract] [Full Text] [PDF]
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F. A Babiker, L. J De Windt, M. van Eickels, C. Grohe, R. Meyer, and P. A Doevendans Estrogenic hormone action in the heart: regulatory network and function Cardiovasc Res, February 15, 2002; 53(3): 709 - 719. [Abstract] [Full Text] [PDF]
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 D. M. Herrington and K. P. Klein Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy J Appl Physiol, December 1, 2001; 91(6): 2776 - 2784. [Abstract] [Full Text] [PDF]
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R. K. Dubey and E. K. Jackson Genome and Hormones: Gender Differences in Physiology: Invited Review: Cardiovascular protective effects of 17{beta}-estradiol metabolites J Appl Physiol, October 1, 2001; 91(4): 1868 - 1883. [Abstract] [Full Text] [PDF]
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 H.-W. Deng, J. Li, J.-L. Li, R. Dowd, K. M. Davies, M. Johnson, G. Gong, H. Deng, and R. R. Recker Association of Estrogen Receptor-{alpha} Genotypes with Body Mass Index in Normal Healthy Postmenopausal Caucasian Women J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2748 - 2751. [Abstract] [Full Text]
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 T. A Kunnas, P. Laippala, A. Penttilä, T. Lehtimäki, and P. J Karhunen Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study BMJ, July 29, 2000; 321(7256): 273 - 274. [Full Text]
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