A Meta-Analysis of the Association of N-Acetyltransferase 2 Gene (NAT2) Variants with Breast Cancer

¹ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH
² Ireland Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH
³ Department of Genetics, Case Western Reserve University, Cleveland, OH

Correspondence to Dr. Robert C. Elston, Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building, Room 1300, 2103 Cornell Road, Cleveland, OH 44106-7281 (e-mail: rce@darwin.epbi.cwru.edu ).

Received for publication September 15, 2006. Accepted for publication January 25, 2007.

The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation
and detoxification pathways. Therefore, NAT2 variants may represent underlying susceptibility to breast cancer. Because a number of studies of the association of NAT2 with breast cancer have been published, the authors performed a meta-analysis. They extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. They summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. The authors identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. They found no evidence for heterogeneity (Cochran’s Q statistic p = 0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio = 1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.

acetyltransferases; breast neoplasms; epidemiology; genotype; meat; NAT2; polymorphism, genetic

Abbreviations: NAT2, N-acetyltransferase 2; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine.

The N-acetyltransferase 2 gene (NAT2) is located on chromosome 8p21.3-23.1 and codes for a phase II xenobiotic metabolizing enzyme (1). The NAT2 enzyme plays an important role in the metabolism of both aromatic and heterocyclic amines, via N- and O-acetylation, which are pathways responsible for deactivation and activation, respectively (2).

A previous NAT2 human genome epidemiology (HuGE) review detailed gene variants and their population frequencies (3). Briefly, NAT2 phenotypes are characterized as being slow, intermediate, or rapid acetylators, which refers to their ability to metabolize or activate xenobiotics.

Previous epidemiologic work implicates NAT2 variants in carcinogenesis, especially for bladder, colon, and breast cancer (3–5). This finding is biologically plausible owing to the ability of the NAT2 enzyme to N-acetylate or O-acetylate carcinogens to inert or noninert compounds capable of forming DNA adducts. Cigarette smoking and intake of well-done meat involve exposure to aryl and heterocyclic amines, substrates of NAT2; therefore, it is plausible that underlying NAT2 genotype may modify risk of cancer based on the ability to activate or detoxify heterocyclic and aromatic amines (6, 7).

Since there have been a number of published reports on NAT2 and breast cancer, we conducted a meta-analysis to summarize the results of the effect on breast cancer of the NAT2 acetylation phenotype and NAT2 genotype and also to discuss evidence for an interaction of NAT2 with exposure to smoking, meat intake, and meat cooking method.

Study selection and inclusion criteria
We searched for relevant papers published before August 2006 by using the Human Genome Epidemiology Network (HuGENet) and the MEDLINE database (National Library of Medicine, Bethesda, Maryland). We searched MEDLINE by using the following terms: "arylamine N-acetyltransferase," "acetyltransferases," "NAT2," "genetic polymorphism," "restriction fragment polymorphism," "single nucleotide polymorphism," "breast cancer," and "breast neoplasms." We included all articles involving case-control or nested case-control studies that investigated NAT2 (determined by using phenotyping or genotyping methods) and breast cancer risk. We also searched the reference lists of the published studies found this way.

Data extraction
We extracted the following information from each manuscript: year of publication, country, number of cases and controls, matching, phenotyping technique, genotyping technique, alleles measured, allele and genotype frequencies, method for phenotype classification, phenotype frequencies, mean age of case and controls, menopausal status, covariates, and results by smoking or meat intake. We also extracted risk estimates for gene-environment interactions.

Classification of phenotype
Because of the inherent differences in methods for measuring NAT2 status—measuring phenotypes by using metabolic response to a particular compound or measuring alleles directly—we did not combine these studies for analysis. Respectively, these two types of studies are herein referred to as "phenotype" or "genotype" studies. Subsequently, we summarized phenotype frequencies (slow and rapid status). In the published genotype studies, individuals were classified as having a slow phenotype if homozygous for any of the slow-activity alleles and as having a rapid phenotype if homozygous or heterozygous for wild-type alleles. In some cases, we reclassified intermediate acetylators as rapid when the authors provided frequencies for an intermediate category (having one slow and one rapid allele) (6).

Statistical analysis
We performed a meta-analysis separately for phenotype and genotype studies. For each analysis, we investigated among-study heterogeneity by using Cochran's Q statistic, and we examined fixed- and random-effect models based on the method of DerSimonian and Laird (8) in Number Cruncher Statistical software (9). We constructed a funnel plot to examine the influence of publication bias.

Phenotype studies
Seven studies were identified that analyzed differences in the proportion of cases and controls having a slow-acetylator phenotype (10–16). Table 1 summarizes these studies. Six were conducted in Europe, and the samples were primarily Caucasian. The sample size ranged from 79 to 515, totaling 1,330 women. Six studies measured acetylation phenotype via administration of arylamine drugs (four sulfamethazine, two dapsone); the other used isoniazid. We pooled the numbers across these studies and calculated the prevalence of the slow-acetylator phenotype to be 56 percent overall: 52 percent in cases and 58 percent in controls.

click to view

Table 1  Description of phenotype-only studies included in a meta-analysis of the association of N-acetyltransferase 2 variants with breast cancer

click to view

Figure 1 Summary plot for phenotype studies (first author, date of publication (reference no.)) and combined estimate of odds ratio and 95% confidence interval. Reference group is rapid acetylators. Studies are sorted according to odds ratio. The sizes of the symbols are proportional to the study sizes.

click to view

Table 2  Description of genotype studies included in a meta-analysis of the association of N-acetyltransferase 2 variants with breast cancer

We reclassified intermediate acetylators as fast acetylators for the analysis in those studies in which the authors classified women into three categories (slow, intermediate, and rapid). Following this reclassification of intermediate phenotypes, we found that, overall, 54.4 percent of cases and 54.3 percent of controls were slow acetylators. From the 16 studies that included primarily Caucasian women and the Caucasian sample provided by Millikan et al. (35), we calculated prevalence of the slow genotype in Caucasians to be 56.9 percent: 57.0 percent in cases and 56.9 percent in controls. For the sample of African-American women, prevalence of the slow phenotype was 40 percent overall: 41 percent for cases and 40 percent for controls (35). In the three Asian studies, the pooled prevalence of the slow phenotype was 20 percent: 21 percent in cases and 18 percent in controls.

Associations
Web table 2 shows that three of the 20 studies reported a significant association between NAT2 acetylation and breast cancer. Alberg et al. (23) showed that rapid-acetylation status increased risk both in the whole sample and among postmenopausal women. Conversely, Sillanpaa et al. (37) in the Finland sample and Huang et al. (29) in the Taiwanese population reported an increased risk for slow acetylators, which may also be highest for postmenopausal women.

For the meta-analysis of the genotype studies, we found no evidence for among-study heterogeneity (Q statistic = 14.58, p = 0.75). Figure 2 shows the individual odds ratios, as well as the summary odds ratio (1.02) and 95 percent confidence interval (0.95, 1.08) for the main effect of NAT2 acetylator genotype obtained by using a fixed-effect model (8).

click to view

Figure 2 Forest plot of genotype studies (first author, date of publication (reference no.)) and combined odds ratio and 95% confidence interval. Reference group is rapid acetylators: those with at least one rapid N-acetyltransferase 2 allele. Studies are sorted according to odds ratio. The sizes of the symbols are proportional to the study sizes.

click to view

Figure 3 Funnel plot of the association of the N-acetyltransferase 2 (NAT2) genotype with breast cancer, by study size. Odds ratios for the main effect of NAT2 are shown. Reference group is rapid acetylators.

Interactions
Smoking.
Of the 15 genotype studies that measured smoking, 13 investigated the hypothesized interaction of smoking and NAT2 acetylator genotype. Some studies further stratified by menopausal status.

Among the studies that examined the NAT2 x smoking interaction according to menopausal status, Ambrosone et al. (24) was the first to show increased risk of breast cancer for slow-acetylating, postmenopausal women who were current or former smokers (using cigarettes/day 2 years ago, cigarettes/day 20 years ago, and lifetime pack-years). These findings were later replicated by Egan et al. (28) (pack-years) and Alberg et al. (23) (active smoking), who reported the strongest association among postmenopausal women. Sillanpaa et al. (37), van der Hel et al. (38), and Matheson et al. (34) reported significant increased risk for smokers who were slow acetylators.

Krajinovic et al. (32), Delfino et al. (27), Hunter et al. (30), and Millikan et al. (35) showed no significant evidence for modification of NAT2 and breast cancer by smoking. Krajinovic et al. reported a nonsignificant increase in risk among rapid acetylators who were current or former smokers, which became significant in the case-only analysis. Delfino et al. reported no trend in risk for rapid or slow acetylators, while Hunter et al.'s weak, nonsignificant trend was among slow acetylators. Millikan et al. reported an increased, yet nonsignificant trend in risk for duration of smoking among postmenopausal rapid acetylators. Interestingly, Chang-Claude et al. (25) reported increased risk of breast cancer in rapid acetylators exposed to passive smoke, a finding later replicated by Morabia et al. (36).

Two of the studies conducted a case-only analysis. Results from Ambrosone et al. (24) suggest that, among cases, the odds of being a slow acetylator were greatest for women who smoked more than 20 cigarettes per day (20 years ago), smoked for more than 20 pack-years, or initiated smoking at an earlier age (≤16 years). Conversely, Krajinovic et al. (32) reported increased odds for being a rapid acetylator for ever smokers.

Meat intake.
There is much published literature on the association of breast cancer with red meat intake and meat doneness (43). Five of the studies included in this review investigated potential modification of the association of NAT2 with breast cancer according to charred or well-done meat intake. The only study that found evidence for interaction between meat doneness and NAT2 status was that of Deitz et al. (26), who reported a significant increasing trend in risk among rapid acetylators with increasing meat doneness score.

Ambrosone et al. (44) reported no significant association between meat consumption and breast cancer, nor did they find evidence of a significant interaction between meat intake and NAT2 acetylation status. Similarly, Gertig et al. (45) found no association of red meat intake or meat cooking method with breast cancer risk in the Nurses' Health Study, and no significant interaction with NAT2. Delfino et al. (46) also found no evidence of increased risk for intake of well-cooked meat nor an interaction with NAT2. The last of the studies, by Krajinovic et al. (32), did not report a significant elevated risk for rapid acetylators who consumed well-done meat. In each of these studies, the trends in risk according to increasing meat intake or charred meat intake were not strong enough to suggest whether NAT2 slow or rapid acetylators are at increased or decreased risk.

Main findings
The results of this meta-analysis show no evidence for an overall effect of NAT2 acetylation capacity on the risk of breast cancer. There is suggestive evidence that acetylation may underlie a susceptibility to breast cancer if there is also exposure to tobacco smoke, but there is little evidence for effect modification by intake of well-done meat. Future studies evaluating gene variants in entire pathways may enable better evaluation of susceptibility to breast cancer in the presence of other factors.

There are a number of challenges in summarizing studies of NAT2 variants; there are not only differences in single nucleotide polymorphism selection and technology available at the time of the study but also a reliance on phenotypic characterization of NAT2 variants. Any misclassification of individuals as slow, intermediate, or rapid acetylators would more likely result in bias toward the null and therefore may partly explain the lack of an overall significant association between NAT2 acetylation status and breast cancer.

Following construction of a funnel plot (figure 3) of both phenotype and genotype studies, we conclude that there is some degree of publication bias in the phenotype studies. These studies were more likely to be published if they found a protective effect for slow acetylators. The distribution of odds ratio estimates in the genotype studies suggests that, in these publications, bias is less likely to have occurred.

Our original goal was to also conduct a quantitative review of the potential factors implicated in modifying the association of NAT2 with breast cancer, specifically smoking and meat intake. However, once we examined the studies and discovered the many different exposure assessments used to classify individuals, we concluded that the difficulty associated with summarizing the effect of different exposure variables would be better overcome by using a pooled design in which primary data are obtained from authors of published manuscripts. At the same time, we found that a pooled analysis, in which the exposure measurements can be better summarized and a more comprehensive analysis performed, is already under way.

Biology
Approximately 26 NAT2 variants are known to exist in humans, some silent and some functional variants responsible for changes in enzymatic activity. An excellent review and explanation of genotype-phenotype correlation was published by Hein et al. (6). This paper helps to clarify the confusion regarding NAT2 allelic nomenclature as well as the functional significance and classification of the different alleles.

For the phenotype studies, our meta-analysis suggests evidence of decreased breast cancer risk for women with a slow phenotype (odds ratio = 0.77, 95 percent confidence interval: 0.62, 0.96) or, conversely, increased breast cancer risk for women with a rapid phenotype (odds ratio = 1.29, 95 percent confidence interval: 1.04, 1.62) when slow is the reference group. The published reports also suggest increased risk for rapid acetylators; however, the majority of these studies were unable to report a significant association. Evans (47) combined the results of Bulovskaya et al. (10) and Cartwright (11) and found an odds ratio of 2.05, suggesting an increased risk for carriers of the rapid allele. These studies were of limited size, however, which may have increased sampling error. In addition, misclassification may also be important because different xenobiotics and methods were used to assess NAT2 activity. The NAT2 phenotype may be influenced by disease status; therefore, the results of the genotype studies may be more reliable because genotype is not affected by disease status.

The genotype studies purport a modifying effect of smoking in the association of NAT2 with breast cancer, especially in postmenopausal women. Postmenopausal women are more likely to have a greater duration of smoking simply because of their age, which may explain these findings. These studies therefore suggest a role for NAT2 in breast cancer carcinogenesis, especially for women who also smoke. This hypothesis can be supported by evidence from Pfau et al. (48), who showed that slow acetylators have a higher quantity of DNA adducts than rapid acetylators. A recent review and meta-analysis of the potential modifying effect of smoking suggests that, among slow acetylators, smoking may increase breast cancer risk, an effect that is strongest among postmenopausal women (odds ratio = 2.4, 95 percent confidence interval: 1.7, 3.3) (49), which agrees with our assessment of the studies included in our review.

The increased risk of breast cancer for women exposed to passive smoke who are also rapid acetylators is very interesting (25, 36) in that passive smoke contains 2-amino-α-carboline, a heterocyclic amine (50). If exposed to passive or sidestream smoke, rapid acetylators are at increased risk since they are more likely to O-acetylate the N-hydroxy heterocyclic amines that have been processed in the liver by CYP1A2 and subsequently form compounds capable of creating DNA adducts (50). Further studies are needed to confirm this association.

Biologically, slow acetylators who have lower concentrations of active NAT2 enzyme and are exposed to aromatic amines are more likely to undergo metabolism via the hydroxylation pathway. This process may then lead to electrophilic intermediates capable of binding DNA and initiating carcinogenesis, as compared with the process in rapid acetylators, whose aromatic amine exposure is metabolized via N-acetylation to become an inactive metabolite (51). Firozi et al. (52) reported a higher frequency of smoking-related adducts in breast cancer cases with the slow-acetylation phenotype, which suggests that the hypothesized increased risk of breast cancer and smoking is especially important for slow acetylators.

The varying action of NAT2 under different exposure scenarios may partially explain the null findings for the main effect of NAT2 and breast cancer. While smoking involves exposure to both aromatic amines and heterocyclic amines, N- and O-acetylation may be taking place. Thus, the competing or heterogeneous nature of the pathway depending on exposure may attenuate the association. In spite of this heterogeneity, many of the studies found evidence of increased risk for slow-acetylating women who also smoke.

Another exposure that has been investigated as a potential modifier of the NAT2 and breast cancer association is meat intake. Meat intake, especially intake of charred meat, is associated with exposure to heterocyclic amines because high meat intake results in increased exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) (53). PhIP is the most abundant heterocyclic amine in cooked meat (53). Women with the rapid-acetylation phenotype and high intake of well-done or charred meat may especially be at increased breast cancer risk, since O-acetylation by NAT2 predominates, resulting in reactive metabolites capable of forming DNA adducts and mutations. Zhu et al. (54) detected PhIP-DNA adducts in breast tissue and reported that rapid acetylators, compared with slow acetylators, had a higher level of PhIP-DNA adducts, conferring increased risk of breast cancer in rapid acetylators who have high exposure to PhIP.

Regarding NAT2, the molecular explanation for why particular exposures more readily result in N- or O-acetylation may be an important cause of the lack of significant main effect of the NAT2 genotype and breast cancer risk. The results of the meta-analysis of the genotype studies are therefore not unexpected. Aryl and heterocyclic amines differ in how they are metabolized, namely, the propensity toward N- or O-acetylation pathways for these respective exposures. Without specific knowledge of which pathway may predominate and whether other genes are involved, it is difficult to discern epidemiologically the exact estimate of risk conferred via one particular gene. Future studies should also measure and analyze the interaction of NAT2 and other genes, such as CYP1A2, in the carcinogen metabolism pathway since knowledge of underlying variation in both genes may more fully characterize an individual's carcinogen metabolism phenotype (55).

Future studies that investigate smoking and meat intake should attempt to collect and use standardized exposure measures. Doing so would greatly help summarize the results of published studies.

This work was supported in part by US Public Health Service National Institutes of Health training grant R25 CA094186 (H. O.-B.), research grants RR03655 and GM28356 (R. E.), and Cancer Center support grant P30CAD43703 (R. E.).

The authors thank Dr. Christine Ambrosone from the Roswell Park Cancer Institute for her constructive comments regarding the manuscript.

Conflict of interest: none declared.

• Table 1
• Table 2
• Web Table 1
• Web Table 2
• Figure 1
• Figure 2
• Figure 3

1. Smith CA, Smith G, Wolf CR. Genetic polymorphisms in xenobiotic metabolism. Eur J Cancer (1994) 30A:1921–35.
2. Hein DW. Acetylator genotype and arylamine-induced carcinogenesis. Biochim Biophys Acta (1988) 948:37–66.
3. Brockton N, Little J, Sharp L, et al. N-acetyltransferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol (2000) 151:846–61.
4. Marcus PM, Hayes RB, Vineis P, et al. Cigarette smoking, N-acetyltransferase 2 acetylation status, and bladder cancer risk: a case-series meta-analysis of a gene-environment interaction. Cancer Epidemiol Biomarkers Prev (2000) 9:461–7.
5. Marcus PM, Vineis P, Rothman N. NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control studies conducted in the general population. Pharmacogenetics (2000) 10:115–22.
6. Hein DW, Doll MA, Fretland AJ, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev (2000) 9:29–42.
7. Weber W. The acetylator genes and drug response. (1987) New York, NY: Oxford University Press.
8. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials (1986) 7:177–88.
9. Number Cruncher Statistical Systems. Kaysville, UT. (www.ncss.com ).
10. Bulovskaya LN, Krupkin RG, Bochina TA, et al. Acetylator phenotype in patients with breast cancer. Oncology (1978) 35:185–8.
11. Cartwright RA. Epidemiological studies on N-acetylation and C-center ring oxidation in neoplasia. Banbury report 16: Genetic variability in responses to chemical exposure. (1984) New York, NY: Cold Spring Harbor Laboratory.
12. Ilett KF, Detchon P, Ingram DM, et al. Acetylation phenotype is not associated with breast cancer. Cancer Res (1990) 50:6649–51.
13. Ladero JM, Fernandez MJ, Palmeiro R, et al. Hepatic acetylator polymorphism in breast cancer patients. Oncology (1987) 44:341–4.
14. Philip PA, Rogers HJ, Millis RR, et al. Acetylator status and its relationship to breast cancer and other diseases of the breast. Eur J Cancer Clin Oncol (1987) 23:1701–6.
15. Sardas S, Cok I, Sardas OS, et al. Polymorphic N-acetylation capacity in breast cancer patients. Int J Cancer (1990) 46:1138–9.
16. Webster DJ, Flook D, Jenkins J, et al. Drug acetylation in breast cancer. Br J Cancer (1989) 60:236–7.
17. Deitz AC, Zheng W, Leff MA, et al. N-Acetyltransferase-2 (NAT2) acetylation polymorphism, well-done meat intake and breast cancer risk among post-menopausal women. (Abstract). Proc Am Assoc Cancer Res (1999) 40:148.
18. Ambrosone CB, Freudenheim JL, Marshall JR, et al. The association of polymorphic N-acetyltransferase (NAT2) with breast cancer risk. Ann N Y Acad Sci (1995) 768:250–2.
19. Chern HD, Huang CS, Wang CY, et al. Association of N-acetyltransferase polymorphism with the susceptibility of breast cancer in Taiwan. (Abstract). Proc Am Assoc Cancer Res (1997) 38:214.
20. Lilla C, Risch A, Kropp S, et al. SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case-control study. Breast Cancer Res (2005) 7:R229–37.
21. van der Hel OL, Bueno-de-Mesquita HB, van Gils CH, et al. Cumulative genetic defects in carcinogen metabolism may increase breast cancer risk (The Netherlands). Cancer Causes Control (2005) 16:675–81.
22. Agundez JA, Ladero JM, Olivera M, et al. Genetic analysis of the arylamine N-acetyltransferase polymorphism in breast cancer patients. Oncology (1995) 52:7–11.
23. Alberg AJ, Daudt A, Huang HY, et al. N-acetyltransferase 2 (NAT2) genotypes, cigarette smoking, and the risk of breast cancer. Cancer Detect Prev (2004) 28:187–93.
24. Ambrosone CB, Freudenheim JL, Graham S, et al. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA (1996) 276:1494–501.
25. Chang-Claude J, Kropp S, Jager B, et al. Differential effect of NAT2 on the association between active and passive smoke exposure and breast cancer risk. Cancer Epidemiol Biomarkers Prev (2002) 11:698–704.
26. Deitz AC, Zheng W, Leff MA, et al. N-Acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women. Cancer Epidemiol Biomarkers Prev (2000) 9:905–10.
27. Delfino RJ, Smith C, West JG, et al. Breast cancer, passive and active cigarette smoking and N-acetyltransferase 2 genotype. Pharmacogenetics (2000) 10:461–9.
28. Egan KM, Newcomb PA, Titus-Ernstoff L, et al. Association of NAT2 and smoking in relation to breast cancer incidence in a population-based case-control study (United States). Cancer Causes Control (2003) 14:43–51.
29. Huang CS, Chern HD, Shen CY, et al. Association between N-acetyltransferase 2 (NAT2) genetic polymorphism and development of breast cancer in post-menopausal Chinese women in Taiwan, an area of great increase in breast cancer incidence. Int J Cancer (1999) 82:175–9.
30. Hunter DJ, Hankinson SE, Hough H, et al. A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis (1997) 18:2127–32.
31. Kocabas NA, Sardas S, Cholerton S, et al. N-acetyltransferase (NAT2) polymorphism and breast cancer susceptibility: a lack of association in a case-control study of Turkish population. Int J Toxicol (2004) 23:25–31.
32. Krajinovic M, Ghadirian P, Richer C, et al. Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. Int J Cancer (2001) 92:220–5.
33. Lee KM, Park SK, Kim SU, et al. N-acetyltransferase (NAT1, NAT2) and glutathione S-transferase (GSTM1, GSTT1) polymorphisms in breast cancer. Cancer Lett (2003) 196:179–86.
34. Matheson MC, Stevenson T, Akbarzadeh S, et al. GSTT1 null genotype increases risk of premenopausal breast cancer. Cancer Lett (2002) 181:73–9.
35. Millikan RC, Pittman GS, Newman B, et al. Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiol Biomarkers Prev (1998) 7:371–8.
36. Morabia A, Bernstein MS, Bouchardy I, et al. Breast cancer and active and passive smoking: the role of the N-acetyltransferase 2 genotype. Am J Epidemiol (2000) 152:226–32.
37. Sillanpaa P, Hirvonen A, Kataja V, et al. NAT2 slow acetylator genotype as an important modifier of breast cancer risk. Int J Cancer (2005) 114:579–84.
38. van der Hel OL, Peeters PH, Hein DW, et al. NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women. Pharmacogenetics (2003) 13:399–407.
39. Wu FY, Lee YJ, Chen DR, et al. Association of DNA-protein crosslinks and breast cancer. Mutat Res (2002) 501:69–78.
40. Lissowska J, Brinton LA, Zatonski W, et al. Tobacco smoking, NAT2 acetylation genotype and breast cancer risk. Int J Cancer (2006) 119:1961–9.
41. Bell DA, Taylor JA, Butler MA, et al. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. Carcinogenesis (1993) 14:1689–92.
42. Lin HJ, Han CY, Lin BK, et al. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology. Am J Hum Genet (1993) 52:827–34.
43. Boyd NF, Stone J, Vogt KN, et al. Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature. Br J Cancer (2003) 89:1672–85.
44. Ambrosone CB, Freudenheim JL, Sinha R, et al. Breast cancer risk, meat consumption and N-acetyltransferase (NAT2) genetic polymorphisms. Int J Cancer (1998) 75:825–30.
45. Gertig DM, Hankinson SE, Hough H, et al. N-acetyl transferase 2 genotypes, meat intake and breast cancer risk. Int J Cancer (1999) 80:13–17.
46. Delfino RJ, Sinha R, Smith C, et al. Breast cancer, heterocyclic aromatic amines from meat and N-acetyltransferase 2 genotype. Carcinogenesis (2000) 21:607–15.
47. Evans D. Acetylation. In: Ethnic differences in reactions to drugs and xenobiotics—Kalow W, Goedde H, Agarwal D, eds. (1986) New York, NY: Alan R Liss, Inc.
48. Pfau W, Stone EM, Brockstedt U, et al. DNA adducts in human breast tissue: association with N-acetyltransferase-2 (NAT2) and NAT1 genotypes. Cancer Epidemiol Biomarkers Prev (1998) 7:1019–25.
49. Terry PD, Goodman M. Is the association between cigarette smoking and breast cancer modified by genotype? A review of epidemiologic studies and meta-analysis. Cancer Epidemiol Biomarkers Prev (2006) 15:602–11.
50. King RS, Teitel CH, Kadlubar FF. In vitro bioactivation of N-hydroxy-2-amino-alpha-carboline. Carcinogenesis (2000) 21:1347–54.
51. Ambrosone CB. Impact of genetics on the relationship between smoking and breast cancer risk. J Women's Cancer (2001) 3:17–22.
52. Firozi PF, Bondy ML, Sahin AA, et al. Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer. Carcinogenesis (2002) 23:301–6.
53. Sinha R, Gustafson DR, Kulldorff M, et al. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a carcinogen in high-temperature-cooked meat, and breast cancer risk. J Natl Cancer Inst (2000) 92:1352–4.
54. Zhu J, Chang P, Bondy ML, et al. Detection of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine-DNA adducts in normal breast tissues and risk of breast cancer. Cancer Epidemiol Biomarkers Prev (2003) 12:830–7.
55. Murtaugh MA, Sweeney C, Ma KN, et al. The CYP1A1 genotype may alter the association of meat consumption patterns and preparation with the risk of colorectal cancer in men and women. J Nutr (2005) 135:179–86.

Provides link to non-governmental sites and does not necessarily represent the views of the Centers  for Disease Control and Prevention.