Increased levels of HDL cholesterol are associated with lower rates of clinical and anatomic atherosclerosis, even in adolescents and young adults. In premenopausal women, estrogen-associated increases in HDL may account for their low rates of coronary heart disease (CHD) events. Recently, a sequence variant in the estrogen receptor-alpha (ER-alpha) gene, ER-alpha IVS1-397 T/C), has been linked to twofold greater increases in HDL cholesterol in response to hormone replacement therapy (HRT). However, it remains unclear whether this sequence variant also augments HDL levels in the setting of premenopausal estrogen exposure and whether such differences translate into greater reductions in atherosclerosis risk. The Pathobiology of Atherosclerosis in Youth (PDAY) study is a large cross-sectional autopsy study of the extent of atherosclerosis in subjects aged 15 to 34 years. The detailed descriptions of atherosclerotic lesions, combined with data on cardiovascular risk factors and access to tissue for DNA extraction, makes this an ideal cohort in which to examine the association between ER-alpha IVS1-397 gentotypes, HDL levels, and development of early atherosclerosis. Therefore we propose to measure the association between the ER-alpha IVS1-397 T/C variant (and several other ER-alpha polymorphisms) and extent of atherosclerosis in the thoracic and abdominal aorta and the right coronary artery in female subjects in the PDAY study (N=700). Secondary aims will include examination of the association between the ER-alpha genotypes and HDL levels, and a determination of whether an association between ER-alpha genotype and extent of disease can be accounted for by genotypic differences in HDL. If the favorable pattern of estrogen effects on HDL and other factors seen in the estimated 20% of women with the ER-alpha IVS1-397 C/C genotype translates into a reduction in risk for atherosclerosis, this information could be used to dramatically improve strategies for use of estrogen for primary prevention of cardiovascular disease.
