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Estrogen receptor-α variants are associated with lipoprotein size distribution and particle levels in women: The Framingham Heart Study

      Abstract

      Plasma lipid profile is affected by endogenous estrogen levels and hormone replacement therapy (HRT). As plasma lipid concentrations have a significant heritable basis and the effects of both endogenous estrogen and use of HRT are mediated by estrogen receptors, we sought to investigate the relationships between polymorphisms in estrogen receptor-α (ESR1) and plasma lipid and lipoprotein concentrations. We analyzed data from 854 women (mean age 52 ± 10 years) from the Framingham Heart Study. A TA repeat in the promoter region, c.30T > C in exon 1, c.454-397T > C, and c.454-351A > G in intron 1, all in linkage disequilibrium (LD), were significantly associated with low-density lipoprotein (LDL) particle size and concentration of small LDL particles. Women with the c.454-397C allele had larger LDL particle size (21.09 ± 0.02 nm versus 21.01 ± 0.03 nm, p = 0.021) concurrent with lower small LDL particle concentration (0.47 ± 0.02 mmol/L versus 0.58 ± 0.03 mmol/L, p = 0.008). Moreover, the TA[L]c.30Cc.454-397Cc.454-351G haplotype (frequency, 32%) was associated with lower small LDL particle concentrations (−0.06 ± 0.03 mmol/L change associated with each copy of this haplotype, p = 0.011) when compared to the TA[S]c.30Tc.454-397Tc.454-351A haplotype (frequency, 46%), where L and S are long and short TA repeats. Our results suggest that common ESR1 polymorphisms have a significant effect on lipoprotein metabolism in women.

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      References

        • Manolagas S.C.
        • Kousteni S.
        Perspective: nonreproductive sites of action of reproductive hormones.
        Endocrinology. 2001; 142: 2200-2204
        • Lavigne M.C.
        • Ramwell P.W.
        • Clarke R.
        Inhibition of estrogen receptor function promotes porcine coronary artery smooth muscle cell proliferation.
        Steroids. 1999; 64: 472-480
        • Snieder H.
        • van Doornen L.J.
        • Boomsma D.I.
        Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins: lessons from twin studies.
        Arterioscler Thromb Vasc Biol. 1999; 19: 2826-2834
        • Matthews K.A.
        • Meilahn E.
        • Kuller L.H.
        • Kelsey S.F.
        • Caggiula A.W.
        • Wing R.R.
        Menopause and risk factors for coronary heart disease.
        New Engl J Med. 1989; 321: 641-646
        • Raza J.A.
        • Reinhart R.A.
        • Movahed A.
        Ischemic heart disease in women and the role of hormone therapy.
        Int J Cardiol. 2004; 96: 7-19
        • Hulley S.
        • Grady D.
        • Bush T.
        • 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.
        J Am Med Assoc. 1998; 280: 605-613
        • Writing Group for the Women's Health Initiative Investigators
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial.
        J Am Med Assoc. 2002; 288: 321-333
        • Hulley S.B.
        • Grady D.
        The WHI estrogen-alone trial—do things look any better?.
        JAMA. 2004; 291: 1769-1771
        • Manson J.E.
        • Hsia J.
        • Johnson K.C.
        • et al.
        Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease.
        N Engl J Med. 2003; 349: 523-534
        • Mendelsohn M.E.
        • Karas R.H.
        The protective effects of estrogen on the cardiovascular system.
        N Engl J Med. 1999; 340: 1801-1811
        • Matsubara Y.
        • Murata M.
        • Kawano K.
        • et al.
        Genotype distribution of estrogen receptor polymorphisms in men and postmenopausal women from healthy and coronary populations and its relation to serum lipid levels.
        Arterioscler Thromb Vasc Biol. 1997; 17: 3006-3012
        • Lu H.
        • Higashikata T.
        • Inazu A.
        • 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
        • Nordstrom P.
        • Glader C.A.
        • Dahlen G.
        • et al.
        Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women.
        J Intern Med. 2003; 254: 140-146
        • Herrington D.M.
        • Howard T.D.
        • Hawkins G.A.
        • 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
        • Feinlieb M.
        • Kannel W.B.
        • Garrison R.J.
        • McNamara P.M.
        • Castelli W.P.
        The Framingham Offspring Study. Design and preliminary data.
        Prev Med. 1975; 4: 518-525
        • Kannel W.B.
        • Feinlieb M.
        • McNamara P.M.
        • Garrison N.J.
        • Castelli W.P.
        An investigacion of coronary heart disease in families: the Framingham Offspring Study.
        Am J Epidemiol. 1979; 110: 281-290
        • Cupples L.A.
        • Gagnon D.R.
        • Kannel W.B.
        Long- and short-term risk of sudden coronary death.
        Circulation. 1992; 85: 111-118
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Gidez L.I.
        • Miller G.J.
        • Burstein M.
        • Slagle S.
        • Eder H.A.
        Separation and quantitation of subclasses of human plasma high density lipoproteins by a simple precipitation procedure.
        J Lipid Res. 1982; 23: 1206-1223
        • Ordovas J.M.
        • Cupples L.A.
        • Corella D.
        • et al.
        Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1323-1329
        • Otvos J.D.
        • Jeyarajah E.J.
        • Bennett D.W.
        • Krauss R.M.
        Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement.
        Clin Chem. 1992; 38: 1632-1638
        • Menasce L.P.
        • White G.R.M.
        • Harrison C.J.
        • Boyle J.M.
        Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique.
        Genomics. 1993; 17: 263-265
        • Ponglikitmongkol M.
        • Green S.
        • Chambon P.
        Genomic organization of the human oestrogen receptor gene.
        EMBO J. 1988; 7: 3385-3388
        • Kos M.
        • Reid G.
        • Denger S.
        • Gannon F.
        Minireview: genomic organization of the human ER-alpha gene promoter region.
        Mol Endocr. 2001; 15: 2057-2063
        • Shearman A.M.
        • Cupples L.A.
        • Demissie S.
        • et al.
        Association between estrogen receptor alpha gene variation and cardiovascular disease.
        JAMA. 2003; 290: 2263-2270
        • Lewontin R.C.
        The interaction of selection and linkage. II. Optimum models.
        Genetics. 1964; 50: 757-782
        • Otvos J.D.
        • Jeyarajah E.J.
        • Cromwell W.C.
        Measurement issues related to lipoprotein heterogeneity.
        Am J Cardiol. 2002; 90: 22i-29i
        • Kuller L.
        • Arnold A.
        • Tracy R.
        • et al.
        Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study.
        Arterioscler Thromb Vasc Biol. 2002; 22: 1175-1180
        • Lehtimaki T.
        • Laaksonen R.
        • Mattila K.M.
        • et al.
        Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men.
        Eur J Clin Invest. 2002; 32: 400-404
        • Herrington D.M.
        • Howard T.D.
        • Brosnihan K.B.
        • et al.
        Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein.
        Circulation. 2002; 105: 1879-1882
        • 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. 2002; 43: 383-391