Abstract
Sex steroid hormones have multiple effects on lipid metabolism. We investigated the association between two common single nucleotide polymorphisms of the estrogen receptor 2 gene (ESR2), 1082G>A and 1730A>G, and PROGINS polymorphism of the progesterone receptor gene (PGR) with lipoprotein levels in a cross-sectional study with 472 women of European descent. The women were classified into three subgroups according to hormonal status, premenopausal women (n=187; mean age=34±9.7 years), postmenopausal women exposed to hormone replacement therapy (HRT) (n=118; 56±6.7 years) and postmenopausal women unexposed to HRT (n=167; 58±9.8 years). The premenopausal and postmenopausal women exposed to HRT, both carriers of G/A genotype, exhibited LDL-C (P=0.027 and 0.001, respectively) and T-chol levels (P=0.035 and 0.001, respectively) lower than carriers of G/G genotype. This association was not observed in postmenopausal women unexposed to HRT. These results suggest that ESR2 1082G>A genotype may influence LDL-C levels in women with abundant estrogen levels, due to either endogenous or exogenous sources.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- BMI:
-
body mass index
- CHD:
-
coronary heart disease
- ERT:
-
estrogen replacement therapy
- ESR1:
-
estrogen receptor 1
- ESR2:
-
estrogen receptor 2
- HDL-C:
-
high-density lipoprotein cholesterol
- HERS:
-
Heart and Estrogen/Progestin Replacement Study
- HRT:
-
hormone replacement therapy
- LDL-C:
-
low-density lipoprotein cholesterol
- PGR:
-
progesterone receptor
- SD:
-
standard deviation
- SNPs:
-
single nucleotide polymorphisms
- T-chol:
-
total cholesterol
- TG:
-
triglyceride
- WHI:
-
Women's Health Initiative
References
Godsland IF . Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001; 75: 898–915.
Rosano GM, Vitale C, Silvestri A, Fini M . Metabolic and vascular effect of progestins in post-menopausal women. Implications for cardioprotection. Maturitas 2003; 46S1: S17–S29.
Kuller LH . Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women's Health Initiative. Arterioscler Thromb Vasc Biol 2003; 23: 11–16.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605–613.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321–333.
Herrington DM, Howard TD . ER-alpha variants and the cardiovascular effects of hormone replacement therapy. Pharmacogenomics 2003; 4: 269–277.
Green S, Walter P, Kumar V, Krust A, Bornert J-M, Argos P et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986; 320: 134–139.
Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G et al. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82: 4258–4265.
Misrahi M, Venencie PY, Saugier-Veber P, Sar S, Dessen P, Milgrom E . Structure of the human progesterone receptor gene. Biochim Biophys Acta 1993; 1216: 289–292.
http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl.
Rosenkranz K, Hinney A, Ziegler A, Hermann H, Fichter M, Mayer H et al. Systematic mutation screening of the estrogen receptor beta gene in probands of different weight extremes: identification of several genetic variants. J Clin Endocrinol Metab 1998; 83: 4524–4527.
Rousseau-Merck MF, Misrahi M, Loosfelt H, Milgrom E, Berger R . Localization of the human progesterone receptor gene to chromosome 11q22-q23. Hum Genet 1987; 77: 280–282.
Rowe SM, Coughlan SJ, McKenna NJ, Garrett E, Kieback DG, Carney DN et al. Ovarian carcinoma-associated TaqI restriction fragment length polymorphism in intron G of the progesterone receptor gene is due to an Alu sequence insertion. Cancer Res 1995; 55: 2743–2745.
Arko B, Prezelj J, Komel R, Kocijancic A, Marc J . No major effect of estrogen receptor beta gene RsaI polymorphism on bone mineral density and response to alendronate therapy in postmenopausal osteoporosis. J Steroid Biochem Mol Biol 2002; 81: 147–152.
Lambert JC, Harris JM, Mann D, Lemmon H, Coates J, Cumming A et al. Are the estrogen receptors involved in Alzheimer's disease? Neurosci Lett 2001; 306: 193–197.
Massart F, Becherini L, Marini F, Noci I, Piciocchi L, Del Monte F et al. Analysis of estrogen receptor (ERalpha and ERbeta) and progesterone receptor (PR) polymorphisms in uterine leiomyomas. Med Sci Monit 2003; 9: BR25–BR30.
Eastwood H, Brown KM, Markovic D, Pieri LF . Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Mol Psychiatry 2002; 7: 86–89.
Tong D, Fabjani G, Heinze G, Obermair A, Leodolter S, Zeillinger R . Analysis of the human progesterone receptor gene polymorphism progins in Austrian ovarian carcinoma patients. Int J Cancer 2001; 95: 394–397.
Wang-Gohrke S, Chang-Claude J, Becher H, Kieback DG, Runnebaum IB . Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50. Cancer Res 2000; 60: 2348–2250.
Kurz C, Tempfer CB, Boecskoer S, Unfried G, Nagele F, Hefler LA . The PROGINS progesterone receptor gene polymorphism and idiopathic recurrent miscarriage. J Soc Gynecol Invest 2001; 8: 295–298.
Manolitsas TP, Englefield P, Eccles DM, Campbell IG . No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer. Br J Cancer 1997; 75: 1398–1399.
Lehtimaki T, Dastidar P, Jokela H, Koivula T, Lehtinen S, Ehnholm C et al. Effect of long-term hormone replacement therapy on atherosclerosis progression in postmenopausal women relates to functional apolipoprotein e genotype. J Clin Endocrinol Metab 2002; 87: 4147–4153.
Tolosa M, Peiro S, Real JT, Cano A, Ascaso JF, Carmena R . The influence of apo E phenotypes on the plasma triglycerides response to hormonal replacement therapy during the menopause. Maturitas 2001; 40: 173–181.
Muhlen D, Barrett-Connor E, Kritz-Silverstein D . Apoliprotein E genotype and response of lipid levels to postmenopausal estrogen use. Atherosclerosis 2002; 161: 209–214.
Yamakawa-Kobayashi K, Somekawa Y, Fujimura M, Tomura S, Arinami T, Hamaguchi H . Relation of the −514C/T polymorphism in the hepatic lipase gene to serum HDL and LDL cholesterol levels in postmenopausal women under hormone replacement therapy. Atherosclerosis 2002; 162: 17–21.
Makela R, Karhunen PJ, Kunnas TA, Ilveskoski E, Kajander OA, Mikkelsson J et al. Myeloperoxidase gene variation as a determinant of atherosclerosis progression in the abdominal and thoracic aorta: an autopsy study. Lab Invest 2003; 83: 919–925.
Lu H, Higashikata T, Inazu A, Nohara A, Yu W, Shimizu M et al. Association of estrogen receptor-alpha gene polymorphisms with coronary artery disease in patients with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2002; 22: 817–823.
Evangelopoulos D, Alevizaki M, Lekakis J, Cimponeriu A, Papamichael C, Kominakis A et al. Molecular analysis of the estrogen receptor alpha gene in men with coronary artery disease: association with disease status. Clin Chim Acta 2003; 331: 37–44.
Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH et al. Association between estrogen receptor alpha gene variation and cardiovascular disease. Obstet Gynecol Surv 2004; 59: 444–445.
Ferrero V, Ribichini F, Matullo G, Guarrera S, Carturan S, Vado A et al. Estrogen receptor-alpha polymorphisms and angiographic outcome after coronary artery stenting. Arterioscler Thromb Vasc Biol 2003; 23: 2223–2228.
Lehtimaki T, Kunnas TA, Mattila KM, Perola M, Penttila A, Koivula T et al. Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med 2002; 80: 176–180.
Nordstrom P, Glader CA, Dahlen G, Birgander LS, Lorentzon R, Waldenstrom A et al. Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med 2003; 254: 140–146.
Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002; 346: 967–974.
Koivu TA, Fan YM, Mattila KM, Dastidar P, Jokela H, Nikkari ST et al. The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women. Maturitas 2003; 44: 29–38.
Kealey C, Reynolds A, Mynett-Johnson L, Claffey E, McKeon P . No evidence to support an association between the oestrogen receptor beta gene and bipolar disorder. Psychiatr Genet 2001; 11: 223–226.
Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003; 12: 205–216.
Parini P, Angelin B, Stavreus-Evers A, Freyschuss B, Eriksson H, Rudling M . Biphasic effects of the natural estrogen 17beta-estradiol on hepatic cholesterol metabolism in intact female rats. Arterioscler Thromb Vasc Biol 2000; 20: 1817–1823.
Parini P, Angelin B, Rudling M . Importance of estrogen receptors in hepatic LDL receptor regulation. Arterioscler Thromb Vasc Biol 1997; 17: 1800–1805.
American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183–1201.
Friedwald WT, Levy RI, Fredrickson DS . Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.
Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.
Abramson JH, Gahlinger PM . Computer Programs for Epidemiologists, PEPI Version 4.0 Sagelbrush Press: Salt Lake City 2001.
Acknowledgements
Thanks are due to Ana Lúcia S. Antunes and Maria Perpétua de O Pinto from the Laboratório de Análises Clínicas da Faculdade de Farmácia. We are also grateful to Fabiana M de Andrade, Fabiano Roldão Silveira, Marilu Fiegenbaum, Marcel Arsand and Vanessa S Mattevi for help in sample collection, and to Dr Sidia M Callegari-Jacques for her advice on the statistical analysis. Financial support was provided by Programa de Apoio a Núcleos de Excelência (PRONEX, Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Almeida, S., Franken, N., Zandoná, M. et al. Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status. Pharmacogenomics J 5, 30–34 (2005). https://doi.org/10.1038/sj.tpj.6500272
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.tpj.6500272
Keywords
This article is cited by
-
Association of estrogen receptor β gene polymorphisms with vascular dementia in women
Neurological Sciences (2012)
-
Association between ESR1 and ESR2 gene polymorphisms and hyperlipidemia in Chinese Han postmenopausal women
Journal of Human Genetics (2010)
-
Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen
Clinical Pharmacology & Therapeutics (2008)
-
Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status
The Pharmacogenomics Journal (2005)