Estrogen receptor-α variants are associated with lipoprotein size distribution and particle levels in women: The Framingham Heart Study
Introduction
Estrogens play key roles in reproductive organs, but also in non-reproductive tissues and organs including the skeleton, the brain, and the cardiovascular system [1]. One of the potential mechanisms by which estrogens influence the health of the cardiovascular system is by their effects on circulating lipoprotein levels [1], [2]. Menopause has been observed to be accompanied by decreases in HDL and increases in LDL that are distinct from those that purely result from increasing age, for example, increases in total cholesterol and triglyceride levels [3], [4]. In addition, consistent with the notion that estrogens play an important role in lipoprotein metabolism, hormone replacement therapy (HRT) has been shown to have favorable effects on lipid profiles [3]. However, despite these observations, the consequent belief that HRT might also have a beneficial effect on cardiovascular disease (CVD) prevention in women has not materialized in the recently reported multicenter prospective studies [5]. The Heart and Estrogen/Progestin Replacement Study (HERS) [6] and the Women's Health Initiative (WHI) Study [7] reveal an increased risk of coronary events among HRT users when compared to women randomly assigned to placebo. These results were observed in both estrogen-plus-progestin regimen and estrogen-alone trials [8]. Although these large randomized trials have provided important information about potential adverse effects of HRT on cardiovascular events, their analyses for the 1-year (and 3-year) follow up period also indicate a beneficial effect of HRT on lipid levels [9].
Estrogen receptors-α and β (ESR1 and ESR2) are estrogen activated transcription factors that are expressed in many tissues [10] and mediate the multiple effects of estrogen, including those on lipids and lipoproteins. Our current limited knowledge of the relationship between variation in the estrogen receptor genes and plasma lipid and lipoprotein levels is from a handful of contrasting and often poorly powered association studies that have yielded various results [11], [12], [13], [14]. Matsubara et al. [11] found no association between ESR1 variants c.454-397T > C (PvuII) and c.454-351A > G (XbaI) and total plasma lipid concentrations (total, LDL, and HDL cholesterol levels) among 87 men and post-menopausal women with myocardial infarction or angina pectoris and 94 controls. While Lu et al. [12] reported that c.454-397T > C and c.454-351A > G were associated with coronary artery disease (CAD) and concentrations of HDL-C in a case control study of 197 men (95 cases) and 98 post-menopausal women (24 cases). Nordstrom et al. [13] reported that in 99 adolescent females, but not among 41 adult women with valvular stenosis or matched controls, that c.454-397T > C was associated with both total cholesterol and LDL-cholesterol levels. Herrington et al. [14] also reported associations between sequence variants in ESR1 and response of HDL-C concentrations to HRT in 309 post-menopausal women with established CAD.
In this study, we examined the relationships between ESR1 polymorphisms and a range of plasma lipid concentration measures (total plasma lipids, subclasses, and particle sizes) using a large sample of women from the Framingham Offspring Study (FOS), a population-based study of risk factors for CVD. Given the central role of estrogen receptors in mediating the influence of estrogens on lipid and lipoprotein levels, we evaluated the hypothesis that variants in the ESR1 gene will be associated with lipid and lipoprotein levels. We also evaluated the hypothesis that the relationship between ESR1 variants and lipids would be different in pre-menopausal women, menopausal women who use HRT, and those who do not use HRT.
Section snippets
Subjects and study design
Subjects were participants in the Framingham Heart Study's offspring component (FOS), a community-based prospective cohort study of risk factors for CVD. The details of the design and methods of the FOS have been published elsewhere [15], [16]. Briefly, in 1971 a total of 5124 subjects, children and spouses of the children of the original Framingham Heart Study participants were enrolled. Nearly all participants of the FOS were Caucasian. These subjects have been followed with examinations
Results
Table 1 displays characteristics of the 854 women included in the current study by menopausal status and HRT use. The mean age was 52 ± 10 years, about 22% were cigarette smokers, and 3% were users of cholesterol lowering medication. Three hundred seventy-five women (44%) were pre-menopausal and 479 (56%) were post-menopausal, including 54 (6% of all women) who were HRT users, and 425 (50% of all women) not HRT users. As expected, age was significantly different among the three groups.
Discussion
We report significant associations between ESR1 variants and lipid profile among pre- and post-menopausal women from the Framingham Offspring Study. In models that adjusted for covariates, about half of the traits evaluated in a detailed lipid profile were significantly associated with one or more of the five ESR1 variants analyzed in this study. In particular, multiple ESR1 variants were associated with lipoprotein size distribution and particle concentrations. This is not at all surprising
Acknowledgements
We would like to thank the participants of the Framingham Study. This work was supported by a National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) Specialized Center of Research in Ischemic Heart Disease (P50 HL63494) and in part by Grants from the NHLBI to DEH (P50-HL63494 and RO1-HL65230). The work is also supported by the NHLBI's Framingham Heart Study (NIH/NHLBI Contract N01-HC-38038 and HL-54776). The Framingham Heart Study is conducted and supported by the
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