A commonly occurring polymorphism upstream of the estrogen receptor alpha alters transcription and is associated with increased HDL.

Journal article

OBJECTIVE: Given the role of estrogen in the regulation of lipid metabolism, we screened for functional polymorphisms in the estrogen receptor alpha (ER*), and examined for their influence on serum cholesterol. METHODS AND RESULTS: We identified a novel C>T polymorphism (ERNE-145), with a minor allele frequency of 41%. This polymorphism was immediately adjacent to a putative glucocorticoid receptor (GR) binding site, which we showed to be functional by electrophoretic mobility shift analysis. The C allele was associated with glucocorticoid-induced reduction in promoter activity compared to control in luciferase reporter studies (p<0.05; n=7). This effect was abolished by the T allele. To investigate the functional significance of ERNE-145, its association with serum cholesterol levels was examined in 1662 post-menopausal women enrolled in the RUTH trial. ERNE-145 genotype (p=0.001), BMI (p<0.001), diabetes mellitus (p<0.001), and ethnicity (p=0.002) were significantly associated with HDL cholesterol. ERNE-145 genotype explained 8.2% of the variability of HDL: each copy of the variant T allele was associated with a 0.041 mmol/L (CI 0.017-0.066) increase in HDL. CONCLUSION: A novel polymorphism upstream of ER* abolished negative transcriptional regulation by an adjacent GR binding sequence, and was strongly associated with HDL levels in a large cohort of post-menopausal women.

Authors: Figtree, G; Grieve, S; Speller, B; Geiger, M; Robinson, BG

• Publication status: Published
• Journal: Atherosclerosis
• Volume: 199
• Issue: 2
• Pages: 354-361
• Publication date: 2008-08-01
• DOI: 10.1016/j.atherosclerosis.2008.02.012
• EISSN: 1879-1484
• ISSN: 0021-9150
• Language: English
• Keywords: Lipoproteins, HDL; Genotype; Middle Aged; Alleles; Transcription, Genetic; Humans; DNA; Cholesterol, HDL; Polymorphism, Genetic; Receptors, Glucocorticoid; Diabetes Mellitus; Estrogen Receptor alpha; Aged; Postmenopause; Female