title: Aromatase gene polymorphisms are associated with survival among patients with cardiovascular disease in a sex-specific manner.
abstract: BACKGROUND
  CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.
  
  
  METHODS
  Caucasian individuals from two independent populations were assessed: 1) a prospective cohort of patients with acute coronary syndromes with 3-year mortality follow-up (n = 568) and 2) a nested case-control study from a randomized, controlled trial of hypertension patients with stable coronary disease in which the primary outcome was death, nonfatal myocardial infarction (MI) or nonfatal stroke (n = 619). Six CYP19A1 SNPs were genotyped (-81371 C>T, -45965 G>C, M201T, R264C, 80 A>G, and +32226 G>A). The sex*genotype interaction term was assessed for the primary outcome and compared by genotype in men and women when a significant interaction term was identified.
  
  
  RESULTS
  We identified a significant interaction between -81371 C>T and sex (p = 0.025) in the ACS population. The variant allele was associated with a 78% increase in mortality in men (HR 1.78, 95% confidence interval [CI] 1.08-2.94) and a nonsignificant 42% decrease in mortality among women (HR 0.58, 95% CI 0.22-1.54). We identified a similar association in the hypertensive CAD group, the -81371 C>T*sex interaction term was p<0.0001, with an associated 65% increase in death, MI, or stroke (HR 1.65, 95% CI 1.00-2.73) in men and a 69% decrease (HR 0.31, 95% CI 0.16-0.6) in women.
  
  
  CONCLUSIONS
  Using two independent populations, this study is the first to document a significant interaction between CYP19A1 genotype and sex on cardiovascular outcomes. These findings could illuminate potential mechanisms of sex differences in cardiovascular disease outcomes.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, College Park, Maryland, United States of America. abeitels@medicine.umaryland.edu
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Megan L
authors.initials: ML
authors.lastname: Hames
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Sharon
authors.initials: S
authors.lastname: Cresci
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: John A
authors.initials: JA
authors.lastname: Spertus
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D054058:Acute Coronary Syndrome / Q000235:genetics; D000368:Aged; D001141:Aromatase / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: D001141:Aromatase