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

Abstract：

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.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Figtree GA,Grieve SM,Speller B,Geiger MJ,Robinson BG,Channon KM,Ragoussis J,Collins P,Watkins H

doi

10.1016/j.atherosclerosis.2008.02.012

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

354-61

issue

2

eissn

0021-9150

issn

1879-1484

pii

S0021-9150(08)00071-3

journal_volume

199

pub_type

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