Abstract
Estrogen was considered to be an important protective factor for cardiovascular diseases in women. Genetic association studies suggested that variations of ESR1and ESR2 genes might have a potential role in lipid profile. Our study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) of ESR1 and ESR2 with hyperlipidemia in Chinese Han postmenopausal women. A total of 443 postmenopausal women aged between 55 and 71 years were recruited from Shanghai, China for a case–control study (154 women with hyperlipidemia and 289 controls). We measured plasma estradiol concentration, glucose and lipid profile levels, evaluated their lifestyle and sequenced four SNPs, namely PvuII (rs2234693) and XbaI (rs9340799) of ESR1 and 1082A>G (rs1256049) and 1730A>G (rs4986938) of ESR2. PvuII (rs2234693) and XbaI (rs9340799) showed significantly different distributions between cases and controls (P=0.002 and P=0.023, respectively). In addition, haplotypes constructed from PvuII–XbaI were also associated with hyperlipidemia (global P=0.012). Haplotypes T–A (P=0.005, odds ratio (OR) 1.52, 95% confidence interval (95% CI): 1.13–2.05) and C–G (P=0.010, OR 0.62, 95% CI: 0.43–0.89) had susceptible and protective effects, respectively. 1082A>G (rs1256049) and 1730A>G (rs4986938) showed no statistical association with hyperlipidemia. In conclusion, our results suggested that ESR1 might have a potential role in hyperlipidemia risk, independent of age, estradiol level, body mass index and lifestyle in Chinese Han postmenopausal women.
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References
Maxwell, S. R. Women and heart disease. Basic Res. Cardiol. 93 (Suppl 2), 79–84 (1998).
Kannel, W. B., Hjortland, M. C., McNamara, P. M. & Gordon, T. Menopause and risk of cardiovascular disease: the Framingham study. Ann. Int. Med. 85, 447–452 (1976).
White, C. R., Shelton, J., Chen, S. J., Darley-Usmar, V., Allen, L., Nabors, C. et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation 96, 1624–1630 (1997).
Campos, H., Walsh, B. W., Judge, H. & Sacks, F. M. Effect of estrogen on very low density lipoprotein and low density lipoprotein subclass metabolism in postmenopausal women. J. Clin. Endocrinol. Metab. 82, 3955–3963 (1997).
Lahm, T., Crisostomo, P. R., Markel, T. A., Wang, M., Wang, Y., Tan, J. et al. Selective estrogen receptor-alpha and estrogen receptor-beta agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide dependent mechanism. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, 486–493 (2008).
Mendelsohn, M. E. & Karas, R. H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340, 1801–1811 (1999).
Losordo, D. W., Kearney, M., Kim, E. A., Jekanowski, J. & Isner, J. M. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 89, 1501–1510 (1994).
Ober, C., Nord, A. S., Thompson, E. E., Pan, L., Tan, Z., Cusanovich, D. et al. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J. Lipid Res. 50, 798–806 (2009).
Herrington, D. M., Howard, T. D., Brosnihan, K. B., McDonnell, D. P., Li, X., Hawkins, G. A. et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 105, 1879–1882 (2002).
Herrington, D. M., Howard, T. D., Hawkins, G. A., Reboussin, D. M., Xu, J., Zheng, S. L. et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N. Engl. J. Med. 346, 967–974 (2002).
Ntukidem, N. I., Nguyen, A. T., Stearns, V., Rehman, M., Schott, A., Skaar, T. et al. Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. Clin. Pharmacol. Ther. 83, 702–710 (2008).
Deng, H. W., Li, J., Li, J. L., Dowd, R., Davies, K. M., Johnson, M. et al. Association of estrogen receptor-alpha genotypes with body mass index in normal healthy postmenopausal Caucasian women. J. Clin. Endocrinol. Metab. 85, 2748–2751 (2000).
Kikuchi, T., Hashimoto, N., Kawasaki, T. & Uchiyama, M. Association of serum low-density lipoprotein metabolism with oestrogen receptor gene polymorphisms in healthy children. Acta. Paediatr. 89, 42–45 (2000).
Schupf, N., Lee, J. H., Wei, M., Pang, D., Chace, C., Cheng, R. et al. Estrogen receptor-alpha variants increase risk of Alzheimer's disease in women with Down syndrome. Dement. Geriatr. Cogn. Disord. 25, 476–482 (2008).
Lehtimaki, T., Kunnas, T. A., Mattila, K. M., 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. 80, 176–180 (2002).
Koivu, T. A., Fan, Y. M., Mattila, K. M., Dastidar, P., Jokela, H., Nikkari, S. T. et al. The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women. Maturitas 44, 29–38 (2003).
Ogawa, S., Emi, M., Shiraki, M., Hosoi, T., Ouchi, Y. & Inoue, S. Association of estrogen receptor beta (ESR2) gene polymorphism with blood pressure. J. Hum. Genet. 45, 327–330 (2000).
Tamura, M., Nakayama, T., Sato, I., Sato, N., Izawa, N., Hishiki, M. et al. Haplotype-based case-control study of estrogen receptor alpha (ESR1) gene and pregnancy-induced hypertension. Hypertens. Res. 31, 221–228 (2008).
Lazaros, L., Markoula, S., Xita, N., Giannopoulos, S., Gogou, P., Lagos, G. et al. Association of estrogen receptor-alpha gene polymorphisms with stroke risk in patients with metabolic syndrome. Acta. Neurologica. Scandinavica. 117, 186–190 (2008).
Xu, H., Hou, X., Wang, N., Hui, B., Jin, J., Yun, S. et al. Gender-specific effect of estrogen receptor-1 gene polymorphisms in coronary artery disease and its angiographic severity in Chinese population. Clinica. Chimica. Acta.; Int. J. Clin. Chem. 395, 130–133 (2008).
Shearman, A. M., Cupples, L. A., Demissie, S., Peter, I., Schmid, C. H., Karas, R. H. et al. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA 290, 2263–2270 (2003).
Schuit, S. C., Oei, H. H., Witteman, J. C., Geurts van Kessel, C. H., van Meurs, J. B., Nijhuis, R. L. et al. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. JAMA 291, 2969–2977 (2004).
Mansur, AdeP., Nogueira, C. C., Strunz, C. M., Aldrighi, J. M. & Ramires, J. A. Genetic polymorphisms of estrogen receptors in patients with premature coronary artery disease. Arch. Med. Res. 36, 511–517 (2005).
Gallagher, C. J., Keene, K. L., Mychaleckyj, J. C., Langefeld, C. D., Hirschhorn, J. N., Henderson, B. E. et al. Investigation of the estrogen receptor-alpha gene with type 2 diabetes and/or nephropathy in African-American and European-American populations. Diabetes 56, 675–684 (2007).
Keene, K. L., Mychaleckyj, J. C., Smith, S. G., Leak, T. S., Perlegas, P. S., Langefeld, C. D. et al. Comprehensive evaluation of the estrogen receptor alpha gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population. Hum. Genet. 123, 333–341 (2008).
Alessio, A. M., Hoehr, N. F., Siqueira, L. H., Ozelo, M. C. & de Padua Mansur, A. Annichino-Bizzacchi J. M. Association between estrogen receptor alpha and beta gene polymorphisms and deep vein thrombosis. Thromb. Res. 120, 639–645 (2007).
Rexrode, K. M., Ridker, P. M., Hegener, H. H., Buring, J. E., Manson, J. E. & Zee, R. Y. Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women. Clin. Chem. 53, 1749–1756 (2007).
Nilsson, M., Naessen, S., Dahlman, I., Linden Hirschberg, A., Gustafsson, J. A. & Dahlman-Wright, K. Association of estrogen receptor beta gene polymorphisms with bulimic disease in women. Mol. Psychiatr. 9, 28–34 (2004).
Almeida, S., Franken, N., Zandona, M. R., Osorio-Wender, M. C. & Hutz, M. H. Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status. Pharmacogenomics J. 5, 30–34 (2005).
Grundy, S. M., Becker, D., Clark, L. T., Cooper, R. S., Denke, M. A., Howard, J. et al. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, 3143–3421 (2002).
Shi, Y. Y. & He, L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 15, 97–98 (2005).
Faul, F., Erdfelder, E., Lang, A. G. & Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods 39, 175–191 (2007).
Di Croce, L., Bruscalupi, G. & Trentalance, A. Independent behavior of rat liver LDL receptor and HMGCoA reductase under estrogen treatment. Biochem. Biophys. Res. Commun. 224, 345–350 (1996).
Mendelsohn, M. E. Protective effects of estrogen on the cardiovascular system. Am. J. Cardiol. 89, 12E–17E; discussion 17E-18E (2002).
Demissie, S., Cupples, L. A., Shearman, A. M., Gruenthal, K. M., Peter, I., Schmid, C. H. et al. Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study. Atherosclerosis 185, 210–218 (2006).
van Meurs, J. B., Schuit, S. C., Weel, A. E., van der Klift, M., Bergink, A. P., Arp, P. P. et al. Association of 5′ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum. Mol. Genet. 12, 1745–1754 (2003).
Schuit, S. C., van Meurs, J. B., Bergink, A. P., van der Klift, M., Fang, Y., Leusink, G. et al. Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms. J. Clin. Endocrinol. Metab. 89, 303–309 (2004).
Weel, A. E., Uitterlinden, A. G., Westendorp, I. C., Burger, H., Schuit, S. C., Hofman, A. et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J. Clin. Endocrinol. Metab. 84, 3146–3150 (1999).
Jones, D. R., Schmidt, R. J., Pickard, R. T., Foxworthy, P. S. & Eacho, P. I. Estrogen receptor-mediated repression of human hepatic lipase gene transcription. J. Lipid Res. 43, 383–391 (2002).
Shearman, A. M., Cooper, J. A., Kotwinski, P. J., Humphries, S. E., Mendelsohn, M. E., Housman, D. E. et al. Estrogen receptor alpha gene variation and the risk of stroke. Stroke 36, 2281–2282 (2005).
Yoshihara, R., Utsunomiya, K., Gojo, A., Ishizawa, S., Kanazawa, Y., Matoba, K. et al. Association of polymorphism of estrogen receptor-alpha gene with circulating levels of adiponectin in postmenopausal women with type 2 diabetes. J. Atheroscler. Thromb. 16, 250–255 (2009).
Hayashi, K., Maeda, S., Iemitsu, M., Otsuki, T., Sugawara, J., Tanabe, T. et al. Sex differences in the relationship between estrogen receptor alpha gene polymorphisms and arterial stiffness in older humans. Am. J. Hypertens. 20, 650–656 (2007).
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. 23, 2223–2228 (2003).
Lamon-Fava, S., Asztalos, B. F., Howard, T. D., Reboussin, D. M., Horvath, K. V., Schaefer, E. J. et al. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women. Clin. Endocrinol. (2009) (e-pub ahead of print; doi:10.1111/j.1365-2265.2009.03644.x).
Pan, A., Franco, O. H., Ye, J., Demark-Wahnefried, W., Ye, X., Yu, Z. et al. Soy protein intake has sex-specific effects on the risk of metabolic syndrome in middle-aged and elderly Chinese. J. Nutr. 138, 2413–2421 (2008).
Domingues-Montanari, S., Subirana, I., Tomas, M., Marrugat, J. & Senti, M. Association between ESR2 genetic variants and risk of myocardial infarction. Clin. Chem. 54, 1183–1189 (2008).
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. 22, 817–823 (2002).
Acknowledgements
We appreciate the contribution of all of the members participating in this study, as well as that of the doctors who helped us in the diagnosis. This study was supported by grants from the National Natural Science Foundation of China, the national S973 and 863 Programs, Chinese Nutrition Society (05015), Dannon Institute, Shanghai-Unilever Research and Development Fund (06SU07007), Shanghai Municipality Science & Technology Commission (05JC14090,07DJ14005, Shanghai Leading Academic Discipline Project (B205), the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences (2007KIP210,2009KIP305) and the Chinese Academy of Sciences (KSCX2-YW-R-01, KSCX2-YW-N-034).
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Zhao, T., Zhang, D., Liu, Y. et al. Association between ESR1 and ESR2 gene polymorphisms and hyperlipidemia in Chinese Han postmenopausal women. J Hum Genet 55, 50–54 (2010). https://doi.org/10.1038/jhg.2009.122
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DOI: https://doi.org/10.1038/jhg.2009.122
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