Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study

Objective To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women. Design In 1780 unrelated members of the community-based Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-α (ESR1), estrogen receptor-β (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors. Results In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women. Conclusions Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.

[1]  J. Gustafsson,et al.  Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β , 2002, Science.

[2]  P. Chambon,et al.  Estrogen Receptor-&agr; Mediates the Protective Effects of Estrogen Against Vascular Injury , 2002, Circulation research.

[3]  C. Allis,et al.  Steroid receptor coactivator-1 is a histone acetyltransferase , 1997, Nature.

[4]  S. Oparil,et al.  Sex hormones and hypertension. , 2002, Cardiovascular research.

[5]  K. Chien,et al.  Relation of systemic arterial pulse pressure to coronary atherosclerosis in patients with mitral stenosis. , 1997, The American journal of cardiology.

[6]  Chen Ming-Fong,et al.  Relation of systemic arterial pulse pressure to coronary atherosclerosis in patients with mitral stenosis , 1997 .

[7]  D. Comings,et al.  Molecular heterosis: a review. , 2000, Molecular genetics and metabolism.

[8]  J. Kato,et al.  Isoform/variant mRNAs for sex steroid hormone receptors in humans , 2003, Trends in Endocrinology & Metabolism.

[9]  G. Giles,et al.  Familial patterns of covariation for cardiovascular risk factors in adults: The Victorian Family Heart Study. , 2000, American journal of epidemiology.

[10]  S. Hukuda,et al.  Estrogen receptor gene polymorphism and generalized osteoarthritis. , 1998, The Journal of rheumatology.

[11]  J. Norris,et al.  Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study , 2003, BMC Genetics.

[12]  R. Fagard,et al.  The impact of genetic and environmental influences on blood pressure variance across age-groups , 2001, Journal of hypertension.

[13]  R. Lewontin.  The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. , 1964, Genetics.

[14]  P. Siiteri,et al.  Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. , 1974, The Journal of clinical endocrinology and metabolism.

[15]  Z. Vajo,et al.  Hormone Replacement Therapy Reduces Mean 24‐Hour Blood Pressure and Its Variability in Postmenopausal Women with Treated Hypertension , 2000, Menopause.

[16]  C. Schmid,et al.  Association between Estrogen receptor α gene variation and cardiovascular disease , 2003 .

[17]  L. Kuller,et al.  The importance of pulsatile components of hypertension in predicting carotid stenosis in older adults , 1997, Journal of hypertension.

[18]  S. Harrap,et al.  Sex-dependent association of blood pressure with oestrogen receptor genes ERalpha and ERbeta. , 2004, Journal of hypertension.

[19]  Anita L. DeStefano,et al.  Evidence for a Gene Influencing Blood Pressure on Chromosome 17: Genome Scan Linkage Results for Longitudinal Blood Pressure Phenotypes in Subjects From the Framingham Heart Study , 2000, Hypertension.

[20]  C. Y. Lee,et al.  Hypertensive response during dobutamine stress echocardiography. , 1997, The American journal of cardiology.

[21]  B. O’Malley,et al.  Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. , 1998, Science.

[22]  R. Lewontin,et al.  THE INTERACTION OF SELECTION AND LINKAGE. II. OPTIMUM MODELS. , 1964, Genetics.

[23]  C. Rotimi,et al.  Heritability of blood pressure in Nigerian families , 2002, Journal of hypertension.

[24]  E. Lange,et al.  Age-stratified heritability estimation in the Framingham Heart Study families , 2003, BMC Genetics.

[25]  Charles Kooperberg,et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. , 2002, JAMA.

[26]  R. Karas,et al.  Molecular and Cellular Basis of Cardiovascular Gender Differences , 2005, Science.

[27]  S. Lehrer,et al.  Estrogen receptor variant and hypertension in women. , 1993, Hypertension.

[28]  S. Harrap,et al.  Sex, Genes And Blood Pressure , 2001, Clinical and experimental pharmacology & physiology.

[29]  D. Levy,et al.  Genome-Wide Scan for Pulse Pressure in the National Heart, Lung and Blood Institute’s Framingham Heart Study , 2004, Hypertension.

[30]  L. Raij,et al.  Postmenopausal hypertension , 2000, Current hypertension reports.

[31]  S. Penckofer,et al.  Estrogen Plus Progestin Therapy: The Cardiovascular Risks Exceed the Benefits , 2003, The Journal of cardiovascular nursing.

[32]  D. Levy,et al.  Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. , 1999, Circulation.

[33]  Daniel Levy,et al.  Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study , 2003, Annals of Internal Medicine.

[34]  D. Levy,et al.  Chorioamnionitis and cerebral palsy in term and near-term infants , 2004 .

[35]  S. Bulun,et al.  Aromatase expression in health and disease. , 1997, Recent progress in hormone research.

[36]  J. Fleg,et al.  Hormone Replacement Therapy and Longitudinal Changes in Blood Pressure in Postmenopausal Women , 2001, Annals of Internal Medicine.

[37]  D. Kiel,et al.  Estrogen Receptor β Polymorphisms Are Associated With Bone Mass in Women and Men: The Framingham Study , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  J. Maccluer,et al.  Genome‐wide linkage analysis of blood pressure in Mexican Americans , 2001, Genetic epidemiology.

[39]  Y. Ouchi,et al.  Association of bone mineral density with polymorphism of the estrogen receptor gene , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  C. Nappi,et al.  Effects of hormonal replacement therapy in postmenopausal hypertensive patients. , 2001, Maturitas.

[41]  M. Yano,et al.  Influence of aortic impedance on the development of pressure-overload left ventricular hypertrophy in rats. , 1996, Circulation.

[42]  J. Melby,et al.  Antihypertensive Effects of an Aromatase Inhibitor in Inbred Salt‐Sensitive Rats , 1991, Hypertension.

[43]  S. Azar,et al.  19-Nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11μ,18,19-hydroxylase activity , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[44]  M. Mendelsohn.  Genomic and nongenomic effects of estrogen in the vasculature. , 2002, The American journal of cardiology.

[45]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.