© 2005 Oxford University Press
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Genetic Variants in the UGT1A6 Enzyme, Aspirin Use, and the Risk of Colorectal Adenoma
Affiliations of authors: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School (ATC.), Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (ATC., DJH., CSF), Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center (ELG, DJH., CSF), Departments of Epidemiology (GJT., ELG, DJH) and Nutrition (ELG, DJH), Harvard School of Public Health, and Department of Medical Oncology, Dana-Farber Cancer Institute (CSF), Boston, MA
Correspondence to: Andrew Chan, MD., MPH, Gastrointestinal Unit, Massachusetts General Hospital GRJ-722, Boston, MA 02114 (e-mail: achan{at}partners.org).
Genetic variation in the uridine diphosphate glucuronosyltransferase 1A6 (UGT1A6) enzyme is associated with impaired metabolism of aspirin. To determine whether polymorphisms in the UGT1A6 enzyme modulate the protective benefit of regular aspirin use on colorectal adenoma, we conducted a prospective, nested case-control study of 1062 women who provided blood specimens and detailed data on aspirin use before undergoing lower endoscopy. All statistical tests were two sided. Although UGT1A6 genotype was not associated with overall adenoma risk (multivariable odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.85 to 1.41), functional variant genotypes statistically significantly modified the effect of aspirin on adenoma (Pinteraction = .02). Among the 616 women with variant genotypes, regular use of aspirin (two or more standard tablets per week) was associated with a decreased risk of adenoma (multivariable OR for adenoma = 0.66 [95% CI = 0.45 to 0.95], OR = 0.63 [95% CI = 0.43 to 0.91] for 0.5–7 standard tablets per week and OR = 0.41 [95% CI = 0.24 to 0.71] for more than 7 tablets per week; Ptrend = .001). In contrast, among women with wild-type genotypes, regular aspirin use was not associated with a reduced risk nor did they obtain any additional benefit with higher doses (Ptrend = .50). These results were consistent among women with advanced adenomas (Pinteraction = .003). Thus, functional polymorphisms in the UGT1A6 enzyme statistically significantly modify the effect of aspirin on colorectal neoplasia, and certain subsets of the population, defined by genotype, may obtain differential benefit from aspirin chemoprevention.
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