Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease

Although endogenous and exogenous estrogens do increase plasma levels of high-density lipoprotein (HDL) cholesterol, their effects vary considerably. Family studies suggest this may in part result from allelic variants inthe gene encoding estrogen receptor-alpha (ER-a), also known as estrogen receptor 1 (ESR1), which may alter its expression or function. This would be consistent with the functionally important gene variants already identified as encoding steroid receptors, such as receptors for androgens, mineralocorticoids, and glucocorticoids. This study examined the relation between 10 sequence variants in ER-a, including two newly identified ER-a polymorphisms, and HDL cholesterol responses to hormone replacement therapy (HRT). Participants were 309 women with coronary artery disease who were enrolled in the Estrogen Replacement and Atherosclerosis Trial. The women received 0.625 mg of conjugated equine estrogen orally each day, estrogen plus 2.5 mg of medroxyprogesterone acetate, or placebo, and were followed for 3.2 years on average. The IVS1-401 C/C genotype was identified in 18.9% of the study population. After adjusting for age, race, diabetes, body mass index, smoking, alcohol intake, and frequency of exercise, these women had HDL cholesterol levels more than twice those found in the other women (13.1 vs. 6 mg/dl). Only the HDL subfraction 3 (HDL3) was affected. This effect was noted in women given combined estrogen/progestin therapy and those receiving estrogen alone as HRT. Similar patterns of response to HRT were noted for three other highly linked ER-a intron 1 polymorphisms close to the VSI-401 site. Despite the favorable changes in HDL cholesterol, angiographically defined coronary artery disease did not progress less rapidly in women bearing the IVSI-401 C/C genotype. None of the other ER-a polymorphisms studied were associated with an altered response of HDL cholesterol to HRT. These findings support the possibility of using genetic screening to reach decisions on HRT to maximize the well-being of postmenopausal women. The actual effects of different ER-a genotypes on clinical cardiovascular events remain to be determined.