Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women.
ABSTRACT Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure.
We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor alpha and estrogen receptor beta (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status.
In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia.
The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.
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ABSTRACT: Increased arterial stiffness and wave reflection have been identified as cardiovascular disease risk factors. In light of significant sex differences and the moderate heritability of vascular function measures, we hypothesized that variation in the genes coding for oestrogen receptors alpha (ESR1) and beta (ESR2) and aromatase (CYP19A1) is associated with aortic stiffness and pressure wave reflection as measured by non-invasive arterial tonometry. In all, 1261 unrelated Framingham Offspring Study participants who attended the seventh examination cycle (mean age 62+/-10 years, 52% women) and had arterial tonometry and genotyping data were included in the study. Analysis of covariance was used to assess the association of polymorphisms with forward wave amplitude, augmented pressure, augmentation index (AI), carotid-femoral pulse wave velocity and mean arterial pressure with adjustment for potential confounders. In the sex-pooled analysis, those homozygous for the minor allele at any of four ESR1 variants that were in strong linkage disequilibrium ((TA)(n), rs2077647, rs2234693 and rs9340799) had on an average 18% higher augmented pressure and 16% greater AI compared with carriers of one or two major alleles (P=0.0002-0.01). A similar magnitude of association was detected in those homozygous for the common allele at two ESR2 single-nucleotide polymorphisms (P=0.007-0.02). Our results are consistent with the hypothesis that variation in ESR1 and ESR2, but not CYP19A1, is associated with an increased wave reflection that may contribute to associations between these variants and adverse clinical events demonstrated earlier. Our findings will need to be replicated in additional cohorts.Journal of human hypertension 03/2009; 23(10):636-44. · 2.80 Impact Factor
Article: Do Estrogen Receptor beta Polymorphisms Play A Role in the Pharmacogenetics of Estrogen Signaling?[show abstract] [hide abstract]
ABSTRACT: Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) alpha and beta. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERalpha polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERbeta in order to provide a functional perspective with potential pharmacogenomic implications.Current pharmacogenomics and personalized medicine. 01/2009; 6(4):239-259.
Article: African American-preponderant single nucleotide polymorphisms (SNPs) and risk of breast cancer.[show abstract] [hide abstract]
ABSTRACT: African American women more often present with more aggressive types of breast cancer than Caucasian women, but little is known whether genetic polymorphisms specific to or disproportionate in African Americans are associated with their risk of breast cancer. A population-based case-control study was conducted including 194 cases identified through the Metropolitan Detroit Cancer Surveillance System and 189 controls recruited through random digit dialing to examine polymorphisms in genes involved in estrogen metabolism and action. The African American-specific CYP1A1 5639C allele was associated with an increased risk of breast cancer (odds ratio (OR)=2.34, 95% confidence interval (CI) 1.23-4.44) and this association with the CYP1A1 5639 locus was dependent on another polymorphism in the CYP3A4 gene (P=0.043 for the interaction). In addition, African American-predominant CYP1B1 432 Val allele was significantly more often found in the cases than in the controls overall and the HSD17B1 312 Gly allele was specifically associated with premenopausal breast cancer risk (OR=3.00, 95%CI 1.29-6.99). These observations need to be confirmed in larger studies due to the limited statistical power of the study based on a small number of cases.Cancer epidemiology. 08/2009; 33(1):24-30.