title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, UK. gfigtree@med.usyd.edu.au
authors: Gemma A
authors: GA
authors: Figtree
authors: Stuart M
authors: SM
authors: Grieve
authors: Bridget
authors: B
authors: Speller
authors: Mary-Jane
authors: MJ
authors: Geiger
authors: Bruce G
authors: BG
authors: Robinson
authors: Keith M
authors: KM
authors: Channon
authors: Jiannis
authors: J
authors: Ragoussis
authors: Peter
authors: P
authors: Collins
authors: Hugh
authors: H
authors: Watkins
mesh_terms: D000368:Aged; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D008076:Cholesterol, HDL; D047628:Estrogen Receptor alpha; D008075:Lipoproteins, HDL; D011965:Receptors, Glucocorticoid; D004247:DNA