Val158Met Polymorphism in catechol-O-methyltransferase gene associated with risk factors for breast cancer.
Extensive mammographic density is heritable, strongly associated with increased breast cancer risk, and is influenced by sex hormone exposure. In a cross-sectional study of 181 pre- and 171 postmenopausal women without breast cancer, we examined the relationship of a functional polymorphism in catechol-O-methyltransferase (COMT; VAL-->MET) to mammographic density and other risk factors for breast cancer. We hypothesized that individuals who inherited the low-activity form of COMT (COMT*2 allele) would have higher levels of breast density, presumably because of reduced inactivation/detoxification of catecholestrogens. Subjects were recruited across five categories of breast density. Risk factor information, anthropometric measures, and blood samples were obtained; sex hormone and growth factor levels were measured, and COMT genotypes determined. Mammograms were digitized and measured using a computer-assisted method. After adjustment for age and ethnicity, among pre- but not postmenopausal subjects, each low-activity COMT*2 allele was associated with lower levels of percentage breast density. The statistical significance of this association was lost after further adjustment for serum growth factors [growth hormone, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3)], hormones [follicle-stimulating hormone (FSH) and progesterone], and body size (body mass index and waist:hip ratio). The low-activity COMT*2 allele was also associated, after adjustment for age and ethnicity in premenopausal women, with lower serum levels of IGF-1, higher levels of FSH and progesterone, and with a larger waist:hip ratio, body mass index, and subscapular skinfold. After adjustment for body size, the associations of genotype with IGFBP-3 and FSH were no longer significant. These findings indicate that COMT genotype is associated with several risk factors for breast cancer and suggest that the low-activity COMT*2 allele is associated with a reduced risk of breast cancer among premenopausal women.
D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D002170:Canada; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003430:Cross-Sectional Studies; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D017698:Postmenopause; D017697:Premenopause; D012307:Risk Factors
D004967:Estrogens; D002394:Catechol O-Methyltransferase