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.
- SourceAvailable from: Victor L Thijssen01/2004;
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ABSTRACT: The purpose of this investigation was to evaluate single nucleotide polymorphism (SNP) variants of the estrogen receptor genes ESR1 and ESR2 and bone mineral density (BMD) of the lumbar spine (LS-BMD) or total hip (hip BMD) in women of 4 races/ethnicities who were premenopausal or in early perimenopause. The sample consisted of 1,301 participants from the Study of Women's Health Across the Nation (SWAN) with measures of BMD and genotyping; of these, 295 were African American, 693 were Caucasian, 151 were Chinese, and 162 were Japanese. We evaluated the potential association of LS-BMD or hip BMD with 4 SNPs from the ESR1 gene (ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, and ESR1 rs3798577), and 3 SNPs from the ESR2 gene (ESR2 rs1255998, ESR2 rs1256030, and ESR2 rs1256065). Unadjusted mean LS-BMD values ranged from 1.141+/-0.14 g/cm(2) in African American women to 1.031+/-0.11 g/cm2 in Japanese women; unadjusted mean hip BMD values ranged from 1.053+/-0.14 g/cm2 in African American women to 0.862+/-0.10 g/cm2 in Chinese women. African American and Japanese women with the ESR1 rs2234693 (PvuII) CC genotype had higher LS-BMDs than did their peers with the TT genotype (P=0.009 and P=0.04, respectively). Japanese women with the ESR1 rs3798577 CC or TC genotypes had lower LS-BMD than did Japanese women with the TT genotype (P=0.02 and P=0.01, respectively). Caucasian women with the TC genotype for ESR2 rs1256030 had lower LS-BMDs than did those with the CC genotype (P=0.02). Chinese women who were heterozygous for ESR2 rs1256030 or ESR2 rs1256065 had significantly higher LS-BMDs and hip BMDs than did the referent groups for each of these SNPs (CC and AA, respectively). Associations between BMD and ESR1 and ESR2 genotypes varied by race/ethnicity and by bone site. Our results differ from those previously reported for 2 ESR1 genotypes (ESR1 rs2234693 [PvuII] and ESR1 rs9340799 [XbaI]). Moreover, 2 ESR1 and 3 ESR2 SNPs we studied have not previously been examined with respect to BMD. Among these, ESR2 rs1256030 and ESR2 rs1256065 appear to have an effect at both the lumbar spine and hip in Chinese women and may warrant further study.The American journal of medicine 10/2006; 119(9 Suppl 1):S79-86. · 4.47 Impact Factor
Article: Molecular heterosis: a review.[show abstract] [hide abstract]
ABSTRACT: Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counterintuitive to the expectation that if the 1 allele of a two-allele polymorphism is associated with a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to 50% of all gene associations. A number of examples are reviewed, including those for the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor. Several examples are given in which the heterosis is gender-specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U-shaped response curve in which either to little or too much gene expression is deleterious, with optimal gene expression occurring in 12 heterozygotes. The second proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score, while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele-based linkage techniques usually miss heterotic associations. Because up to 50% of association studies show a heterosis effect, this can significantly diminish the power of family-based linkage and association studies.Molecular Genetics and Metabolism 01/2000; 71(1-2):19-31. · 2.83 Impact Factor