1. ¹Biostatistics Research Center, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, Massachusetts
2. ²Molecular Cardiology Research Institute, Department of Medicine and the Tufts-New England Medical Center SCOR in Ischemic Heart Disease, Tufts-New England Medical Center, Boston, Massachusetts
3. ³Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
4. ⁴National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts
5. ⁵Biostatistics Department, Boston University School of Public Health, Boston, Massachusetts

Correspondence: Dr. Inga Peter, Tufts-New England Medical Center, 750 Washington Street, NEMC #63 Boston, MA 02111 E-mail: ipeter@tufts-nemc.org

^*This study was supported by National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI) Specialized Center of Research in Ischemic Heart Disease P50 HL63494; NIH/NHLBI Contract N01-HC-38038 and N01-HC-25195; NIH/NHLBI Program Project Grant P01-HL077378.

Received 3 January 2005; Revised 8 April 2005; Accepted 12 May 2005.

Abstract

Background: 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.

Methods: 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 and estrogen receptor (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.

Results: 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.

Conclusions: 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.