Abstract 2323: A Commonly Occurring Estrogen Receptor Alpha Promoter Polymorphism Alters Transcriptional Regulation And Is Associated With Increased HDL Levels
Objectives: Given the role of estrogen in the regulation of lipid metabolism, we examined the influence of genetic variants in the estrogen receptor alpha (ERalpha) on serum cholesterol levels.
Methods/Results: DHPLC and sequencing of the ERalpha gene identified a novel C>T polymorphism located 145 bp upstream of the ER negative element (ERNE-145), with a minor allele frequency of 41%. This polymorphism was immediately adjacent to a putative glucocorticoid response element (GRE), which we showed to be functional by electrophoretic mobility shift analysis. When the sequence spanning the GRE and ERNE-145 was cloned upstream of a basic promoter containing luciferase reporter gene, the presence of the wild-type C allele was associated with a glucocorticoid-induced reduction in promoter activity compared to unstimulated control (p<0.05; n=7). This effect was abolished by the presence of the T allele. In order to investigate the functional significance of ERNE-145, its association with serum cholesterol levels was examined in 1662 postmenopausal women enrolled in the RUTH trial. Linear regression analysis demonstrated that ERNE-145 genotype (p<0.001), BMI (p<0.001), diabetes mellitus (p=0.001), and ethnic origin (p=0.002) were significantly associated with HDL cholesterol. ERNE-145 genotype explained 8.2% of the variability of HDL in this model with an apparent “dose-dependent” effect: each copy of the variant C allele was associated with a 1.6 mg/dL (CI: 0.67–2.58 mg/dL) increase in HDL.
Conclusion: We observed a strong association between the ERNE-145 promoter polymorphism and HDL levels in a large cohort of postmenopausal women, which may be a result of altered regulation of ERalpha expression.