ORIGINAL CONTRIBUTIONS Epidemiology
Association of Estrogen Receptor ? Gene
Polymorphisms With Left Ventricular
Mass and Wall Thickness in Women
Inga Peter, Amanda M. Shearman, Ramachandran S. Vasan,
Deborah R. Zucker, Christopher H. Schmid, Serkalem Demissie,
L. Adrienne Cupples, Jeffrey T. Kuvin, Richard H. Karas,
Michael E. Mendelsohn, David E. Housman, and Emelia J. Benjamin
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 Fra-
mingham Heart Study. Eight single nucleotide polymor-
phisms 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 treat-
ment, 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 poly-
tific interest in investigating LVH determinants. Whereas
hypertension is one of the leading causes of LVH, only
about 25% of patients with hypertension have this disor-
morphisms, 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 lipopro-
tein levels, or hyperglycemia.
Conclusions: The ESR2 polymorphisms are associ-
ated with LV structural differences in women with hyper-
tension 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.
1388–1395 © 2005 American Journal of Hypertension,
Am J Hypertens 2005;18:
Key Words: Left ventricular hypertrophy, estrogen
receptors, echocardiography, polymorphisms (genetics),
ndividuals with left ventricular hypertrophy (LVH)
are predisposed to the development of stroke,1,2
heart failure,2and death,2,3leading to intense scien-
der.4Hypertension, and the other established risk factors
including excess weight and diabetes, only account for
25% to 50% of interindividual variability in left ventric-
ular mass (LVM).5,6Much of the unaccounted variability
may result from specific inherited genetic causes. Herita-
bility has been estimated to account for about 25% to 50%
Received January 3, 2005. First decision April 8, 2005. Accepted May
From the Biostatistics Research Center, Institute for Clinical Re-
search and Health Policy Studies (IP, DRZ, CHS), and Molecular Car-
diology Research Institute, Department of Medicine and the Tufts-New
England Medical Center SCOR in Ischemic Heart Disease (JTK, RHK,
MEM), Tufts-New England Medical Center, Boston, Massachusetts;
Center for Cancer Research, Massachusetts Institute of Technology
(AMS, DEH), Cambridge, Massachusetts; National Heart, Lung, and
Blood Institute’s Framingham Heart Study (RSV, EJB), Framingham,
Massachusetts, and Biostatistics Department, Boston University School
of Public Health (SD, LAC), Boston, Massachusetts.
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 Con-
tract N01-HC-38038 and N01-HC-25195; NIH/NHLBI Program Project
Address correspondence and reprint requests to Dr. Inga Peter,
Tufts-New England Medical Center, 750 Washington Street, NEMC
#63 Boston, MA 02111; e-mail: email@example.com
© 2005 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
by guest on October 30, 2015
34. Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P,
Mendelsohn ME: Estrogen receptor-alpha mediates the protective ef-
fects of estrogen against vascular injury. Circ Res 2002;90:1087–1092.
35. Brouchet L, Krust A, Dupont S, Chambon P, Bayard F, Arnal JF:
Estradiol accelerates reendothelialization in mouse carotid artery
through estrogen receptor-alpha but not estrogen receptor-beta. Cir-
36. Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J, Shaul
PW, Thoren P, Smithies O, Gustafsson JA, Mendelsohn ME: Ab-
normal vascular function and hypertension in mice deficient in
estrogen receptor beta. Science 2002;295:505–508.
37. Pendaries C, Darblade B, Rochaix P, Krust A, Chambon P, Korach KS,
Bayard F, Arnal JF: The AF-1 activation-function of ERalpha may be
dispensable to mediate the effect of estradiol on endothelial NO pro-
duction in mice. Proc Natl Acad Sci U S A 2002;99:2205–2210.
38. Sudhir K, Chou TM, Messina LM, Hutchison SJ, Korach KS, Chatterjee
K, Rubanyi GM: Endothelial dysfunction in a man with disruptive muta-
tion in oestrogen-receptor gene. Lancet 1997;349:1146–1147.
39. Sudhir K, Chou TM, Chatterjee K, Smith EP, Williams TC, Kane
JP, Malloy MJ, Korach KS, Rubanyi GM: Premature coronary
artery disease associated with a disruptive mutation in the estrogen
receptor gene in a man. Circulation 1997;96:3774–3777.
40. Williams JK, Adams MR, Klopfenstein HS: Estrogen modulates
responses of atherosclerotic coronary arteries. Circulation 1990;81:
41. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks
FM: Effects of postmenopausal estrogen replacement on the con-
centrations and metabolism of plasma lipoproteins. N Engl J Med
42. Basile J: Analysis of recent papers in hypertension. Post menopausal
hormone replacement therapy prevents diabetes. J Clin Hypertens
43. Comings DE, MacMurray JP: Molecular heterosis: a review. Mol
Genet Metab 2000;71:19–31.
44. Ushiyama T, Ueyama H, Inoue K, Nishioka J, Ohkubo I, Hukuda S:
Estrogen receptor gene polymorphism and generalized osteoarthri-
tis. J Rheumatol 1998;25:134–137.
45. Ogawa S, Emi M, Shiraki M, Hosoi T, Ouchi Y, Inoue S: Associ-
ation of estrogen receptor beta (ESR2) gene polymorphism with
blood pressure. J Hum Genet 2000;45:327–330.
46. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN:
Meta-analysis of genetic association studies supports a contribution
of common variants to susceptibility to common disease. Nature
AJH–November 2005–VOL. 18, NO. 11 ESTROGEN GENES AND LEFT VENTRICULAR STRUCTURE
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