title: Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.
abstract: BACKGROUND
  After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.
  
  
  RESULTS
  We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex.
  
  
  CONCLUSIONS
  We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.
authors: Cardiovascular Epidemiology and Genetics Group, Institut Municipal d'Investigació Mèdica, Barcelona, Spain. glucas@imim.es
authors: Gavin
authors: G
authors: Lucas
authors: Carla
authors: C
authors: Lluís-Ganella
authors: Isaac
authors: I
authors: Subirana
authors: Mariano
authors: M
authors: Sentí
authors: Christina
authors: C
authors: Willenborg
authors: Muntaser D
authors: MD
authors: Musameh
authors: Stephen M
authors: SM
authors: Schwartz
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Olle
authors: O
authors: Melander
authors: Veikko
authors: V
authors: Salomaa
authors: Roberto
authors: R
authors: Elosua
mesh_terms: D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha