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Variation in Estrogen-Related Genes Associated with Cardiovascular Phenotypes and Circulating Estradiol, Testosterone, and Dehydroepiandrosterone Sulfate Levels

Center for Genetic Epidemiology and Modeling, Institute for Clinical Research and Health Policy Studies (I.P.), and Molecular Cardiology Research Institute (A.K.-H., G.S.H., R.H.K., M.E.M.), Tufts Medical Center, Boston, Massachusetts 02111; Center for Cancer Research (D.E.H.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; National Heart, Lung, and Blood Institute’s Framingham Heart Study (D.L., J.M.M., C.S.F.), Framingham, Massachusetts 01702; Biostatistics Department (L.A.C.), Boston University School of Public Health, Boston, Massachusetts 02115; Department of Preventive Medicine and Cardiology (D.L., J.M.M), Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts 02118; and the Center for Population Studies (D.L.), National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Inga Peter, Ph.D., Assistant Professor of Medicine, Tufts Medical Center, 800 Washington Street, Box no. 63 Boston, Massachusetts 02111. E-mail: ipeter{at}tuftsmedicalcenter.org.

Background: Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors (ESR1) and β (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels.

Methods: Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles.

Results: In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005–0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)_n [L]-rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A]-(TTTA)_n [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)_n long allele and rs1256031 [C] allele had moderately higher estradiol levels (P 0.03). No significant associations with the ESR1 variants were detected.

Conclusions: Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals.