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

Figtree, Gemma A.; Grieve, Stuart M.; Speller, Bridget; Geiger, Mary-Jane; Robinson, Bruce G.; Channon, Keith M.; Ragoussis, Jiannis; Collins, Peter; Watkins, Hugh

doi:10.1016/j.atherosclerosis.2008.02.012

« Previous Next »Atherosclerosis
Volume 199, Issue 2 , Pages 354-361, August 2008

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

Gemma A. Figtree
- Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, UK
- Kolling Institute of Medical Research, University of Sydney, Australia
- Corresponding author at: Department of Cardiology, Royal North Shore Hospital, University of Sydney, St Leonards, NSW 2065, Australia. Tel.: +61 2 9926 7111; fax: +61 2 9906 1355.
Stuart M. Grieve
- Kolling Institute of Medical Research, University of Sydney, Australia
Bridget Speller
- Kolling Institute of Medical Research, University of Sydney, Australia
Mary-Jane Geiger
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States
Bruce G. Robinson
- Kolling Institute of Medical Research, University of Sydney, Australia
Keith M. Channon
- Kolling Institute of Medical Research, University of Sydney, Australia
Jiannis Ragoussis
- Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, UK
Peter Collins
- Cardiac Medicine, National Heart and Lung Institute, Imperial College, London, UK
Hugh Watkins
- Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, UK

Received 1 December 2007; received in revised form 2 February 2008; accepted 3 February 2008. published online 27 March 2008.

Abstract

Objective

Given the role of estrogen in the regulation of lipid metabolism, we screened for functional polymorphisms in the estrogen receptor alpha (ERα), 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 0.041mmol/L (CI 0.017–0.066) increase in HDL.

Conclusion

A novel polymorphism upstream of ERα 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.

Keywords: Estrogen receptor, Hormone, Polymorphism, HDL cholesterol, Genetics