title: Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.
abstract: BACKGROUND
  Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels.
  
  
  METHODS
  Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles.
  
  
  RESULTS
  In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005-0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)(n) [L]-rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A]-(TTTA)(n) [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)(n) long allele and rs1256031 [C] allele had moderately higher estradiol levels (P < or = 0.03). No significant associations with the ESR1 variants were detected.
  
  
  CONCLUSIONS
  Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals.
authors.affiliation: Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA. ipeter@tuftsmedicalcenter.org
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: Alyson
authors.initials: A
authors.lastname: Kelley-Hedgepeth
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000209:etiology*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood*; D004958:Estradiol / Q000097:blood*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D013739:Testosterone / Q000097:blood*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013739:Testosterone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D001141:Aromatase