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N-Acetyltransferase 1 Genetic Polymorphism, Cigarette Smoking, Well-Done Meat Intake, and Breast Cancer Risk¹

Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, Minnesota 55454 [W. Z., D. R. C., T. A. S., A. R. F.]; University of South Carolina School of Public Health and South Carolina Cancer Center, Columbia, South Carolina 29203 [W.Z., W-Q. W.]; Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202 [A. C. D., D. W. H.]; Department of Preventive Medicine and Environmental Health, University of Iowa College of Medicine, Iowa City, Iowa 52242 [J. R. C.]; and Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292 [D. W. H.]

N-Acetyltransferase 1 (NAT1), encoded by the polymorphic NAT1 gene, has been shown to be one of the major enzymes in human breast tissue that activates aromatic and heterocyclic amines. Humans are mainly exposed to these carcinogens through cigarette smoking and consumption of well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who smoke or consume high levels of well-done meat, a nested case-control study was conducted in a prospective cohort study of 41,837 postmenopausal Iowa women. Information on cigarette smoking and other breast cancer risk factors was obtained at the baseline survey conducted in 1986. DNA samples and information on the consumption of well-done meat were obtained, in the case-control study, from breast cancer cases diagnosed from 1992 to 1994 and a random sample of cancer-free cohort members. Genomic DNA samples obtained from 154 cases and 330 controls were assayed for 11 NAT1 alleles (NAT1*3, *4, *5, *10, *11, *14, *15, *16, *17, *19, and *22). The NAT1*4 allele was the predominant allele observed in this study population, accounting for 73.2% (72.4% in cases versus 73.8% in controls) of the total alleles analyzed. Compared to controls, breast cancer cases had a slightly higher frequency of the NAT1*10 allele (18.8% in cases versus 17.3% in controls) and a substantially higher frequency of the NAT1*11 allele (3.6% versus 1.2%). In multivariate analyses, we found a 30% [95% confidence interval (CI) = 0.8–1.9] elevated risk of breast cancer associated with the NAT1*10 allele and a nearly 4-fold (95% CI = 1.5–10.5) elevated risk associated with the NAT1*11 allele. The positive association of breast cancer with the NAT1*11 allele was more evident among smokers [odds ratio (OR) = 13.2, 95% CI = 1.5–116.0] and those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1–33.2) or consistently consumed their red meat well done (OR = 5.6, 95% CI = 0.5–62.7). The association of the NAT1*10 allele with breast cancer was mainly confined to former smokers (OR = 3.3, 95% CI = 1.2–9.5). These findings are consistent with a role for the NAT1 gene in the etiology of human breast cancer.

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