Aromatase gene polymorphisms are associated with survival among patients with cardiovascular disease in a sex-specific manner

• Published in: PloS one Vol. 5; no. 12; p. e15180
• Main Authors: Beitelshees, Amber L, Johnson, Julie A, Hames, Megan L, Gong, Yan, Cooper-Dehoff, Rhonda M, Wu, Jun, Cresci, Sharon, Ma, Cynthia X, Pepine, Carl J, Province, Michael A, Spertus, John A, McLeod, Howard L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-12-2010; Public Library of Science (PLoS)
• Subjects: Acute Coronary Syndrome - genetics; Aged; Androgens; Aromatase; Aromatase - genetics; Biology; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cardiovascular Diseases - mortality; Case-Control Studies; Cerebral infarction; Cohort Studies; Confidence intervals; Cytochrome P-450; Disease control; Drosophila; Estrogens; Female; Gender aspects; Genetic aspects; Genetic diversity; Genetic polymorphisms; Genomics; Health risk assessment; Heart attack; Heart diseases; Humans; Hypertension; Hypertension - drug therapy; Hypertension - genetics; Infarction; Male; Medical research; Medicine; Men; Middle Aged; Mortality; Myocardial infarction; Patient outcomes; Patients; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population genetics; Population studies; Populations; Sex; Sex differences; Sex Factors; Single-nucleotide polymorphism; Stroke; Survival; Treatment Outcome; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015180

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.
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.
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.
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.