Mol Biol Rep (2012) 39:8813–8819
DOI 10.1007/s11033-012-1744-3
NAT2 polymorphisms with oral carcinoma susceptibility:
a meta-analysis
Xian-Lu Zhuo • Jun-Jun Ling • Yan Zhou •
Hou-Yu Zhao • Yu-Feng Song • Ying-Hui Tan
Received: 20 December 2011 / Accepted: 7 June 2012 / Published online: 22 June 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Published data have implicated NAT2 poly-
morphisms as risk factors for various cancers. A number of
studies have focused on the association of NAT2 poly-
morphisms with susceptibility to oral carcinoma and have
yielded inconclusive results. The aim of the present study
was to derive a more precise estimation of the relationship.
We first carried out a deliberate search in the databases
without a language limitation, covering all papers pub-
lished up to Dec 2011. A total of seven case–control studies
including 1,379 cases and 1,868 controls were selected and
the relevant data were extracted for systematic meta-anal-
yses. No significant association was found for the overall
data (OR: 1.04, 95 % CI: 0.79–1.39). In subgroup analyses
according to ethnicity, slow acetylators might increase oral
cancer risk among Asians (OR: 1.38, 95 % CI: 1.04–1.82)
but not Caucasians or Mixed races. The data suggested that
NAT2 polymorphisms might be a low-penetrant risk factor
for oral carcinoma in Asians.
Keywords NAT2
Oral carcinoma
Meta-analysis

Polymorphism
Susceptibility
X.-L. Zhuo
Y. Zhou
Y.-H. Tan (&)
Department of Stomatology, Xinqiao Hospital,
Third Military Medical University, Chongqing, China
e-mail: sydtyh@yahoo.com.cn
X.-L. Zhuo
H.-Y. Zhao
Y.-F. Song (&)
Affiliated Hospital of Guiyang Medical College,
Guiyang 550004, China
e-mail: gysyf@yahoo.com.cn
J.-J. Ling
Department of Otolaryngology, Southwest Hospital,
Third Military Medical University, Chongqing, China
Introduction
Oral carcinoma is one of the ten most frequent cancers
worldwide and complex interactions between many genetic
and environmental factors are considered as its major cause.
Increasing epidemiological evidence suggests that cigarette
smoking and alcohol [1] consumption as well as betel quid
chewing [2] are probably important etiological factors
contributing to oral carcinoma. Some environmental
chemical pollution, widely spread carcinogens, is difficult to
be degraded in the environment and thus might have a long-
term effect on human health. Nevertheless, though many
individuals exposed to environmental risk factors and/or
with extensive tobacco, alcohol consumption and betel quid
chewing, oral cancer develops only in a small proportion of
exposed people, indicating that genetic factors might play a
critical role in the carcinogenic mechanisms.
Oral tissue is prone to be influenced by external toxin
due to its direct exposure. Previous molecular epidemiol-
ogic studies investigating biomarkers have focused on the
research of inter-individual variation in human cancer risk.
Recent evidence [3, 4] indicates that carcinogen-metabo-
lizing genes and DNA-repair genes may play critical roles
in determining individual susceptibility to cancers. Sus-
ceptibility to cancer is determined by the activation of
enzymes involved in carcinogen activation or deactivation.
Polymorphisms in these genes encoding the enzymes,
possibly by altering their expression and function, may
increase or decrease carcinogen activation/detoxication and
modulate DNA repair.
Xenobiotics can be bio-activated into ultimate carcino-
gens by phase I enzymes and subsequently detoxified by
phase II enzymes, such as CYP1A1 and GSTM1 respec-
tively [5]. Polymorphisms of these genes may be associated
with cancer risk. Acetylation is an important route of
123
8814
biotransformation for these chemicals. In human, the N-
acetyltransferase 2 (NAT2) gene encodes phase II enzymes
that play an essential role in the metabolism of aromatic,
heterocyclic amines and hydrazines via N-acetylation and
O-acetylation [6]. Alteration of NAT2 acetylator status
caused by polymorphisms in NAT2 gene had been thought
to decrease enzymatic activity and result in absence of
efficiency in detoxification, thus leading to an increase in
cancer susceptibility [7]. So far, several NAT2 genetic
variants have been identified in human, in which NAT2*4
has been regarded as the most common allele that is linked
with rapid acetylation. Also, NAT2*11A, NAT2*12A,
NAT2*13A as well as NAT2*18 have been classified as
rapid alleles. Conversely, the rest of the alleles are con-
sidered as slow alleles [8–10].
Previous published studies have focused on NAT2
genetic variation with respect to oral cancer and have
yielded conflicting results. Whether NAT2 polymorphism
is a risk factor for oral cancer remains uncertain. As a
single study may have been underpowered in clarifying the
association of NAT2 polymorphisms with oral carcinoma
susceptibility, in the present study we performed evidence-
based quantitative meta-analyses of the published studies
to derive a more precise estimation of the association.
Materials and methods
Literature search strategy for identification
of the studies
We carried out a search in the Medline, EMBASE, OVID,
Sciencedirect, Google Scholar and Chinese National
Knowledge Infrastructure (CNKI) without a language
limitation, covering all papers published up to Dec 2011,
with a combination of the following keywords: NAT2,
Nacetyltransferase 2, oral, head and neck, carcinoma,
neoplasm, tumor, cancer and polymorphism.
We evaluated potentially associated publications by
checking their titles and abstracts and then procured the most
relevant publications for a closer examination. Moreover,
the reference lists of the selected papers were also screened
for other potential articles that possibly have been missed in
the initial search. The following criteria were used for the
literature selection for the further meta-analysis:
1. Studies concerning the association of NAT2 polymor-
phism with oral carcinoma;
2. Observational studies (case–control or cohort studies);
3. Papers must offer the size of the sample, odds ratios
(ORs) and their 95 % confidence intervals (CIs), the
genetic distribution or the information that can help
infer the results.
123
Mol Biol Rep (2012) 39:8813–8819
Accordingly, the following exclusion criteria were also
used:
1. The design and the definition of the experiments were
obviously different from those of the selected papers.
2. The source of cases and controls and other essential
information were not offered;
3. Reviews and duplicated publications.
After searching, we reviewed all papers in accordance
with the criteria defined above for further analysis.
Data extraction
Data were extracted and entered into a database. The extrac-
tion was performed by two reviewers independently. For
conflicting evaluations, an agreement was reached following a
discussion. If a consensus could not be reached, another author
was consulted to resolve the dispute and then a final decision
was made by the majority of the votes. The extracted infor-
mation was entered into a database. Carriers with at least one
of the high-activity alleles were identified as rapid acetylators
and individuals carrying both two low-activity alleles were
classified as slow acetylators. For data not provided in the
main text, the relevant information was obtained by contacting
corresponding authors as possible as we could.
Statistical analysis
OR of NAT2 polymorphisms and oral cancer risk was esti-
mated for each study. For detection of any possible sample
size biases, the OR and its 95 % confidence interval (CI) to
each study was plotted against the number of participants
respectively. A Chi-square based Q statistic test was per-
formed to assess heterogeneity. If the result of the hetero-
geneity test was P [ 0.1, ORs were pooled according to the
fixed-effect model (Mantel–Haenszel). Otherwise, the ran-
dom-effect model (DerSimonian and laird) was used. The
significance of the pooled ORs was determined by Z test.
Publication bias was assessed by visual inspection of
funnel plots [11], in which the standard error of log (OR) of
each study was plotted against its log (OR). An asymmetric
plot indicates a possible publication bias. The symmetry of
the funnel plot was further evaluated by Egger’s linear
regression test [12]. Statistical analysis was undertaken
using the program Review Manager 4.2 and STATA 11.0
software (Stata Corporation, Texas).
Results
Literature search and meta-analysis databases
A total of 27 studies were searched and screened for
retrieval, of which seventeen irrelevant studies were
Mol Biol Rep (2012) 39:8813–8819 8815

As shown in Table 2, the distributions of NAT2 geno-

type classified as rapid or slow acetylators according to the
primary literature were also presented.

Test of heterogeneity

The data in Figs. 2 and 3 concerned the association

between NAT2 polymorphism and oral carcinoma risk. As
shown in the figures, we analyzed the heterogeneity of slow
versus rapid acetylators and the P values were less than 0.1.
Thus, random-effect models were used.
Additionally, I2 value is another index for the hetero-
geneity test [23], with value less than 25 % indicating low,
25–50 % indicating moderate, and greater than 50 %
indicating high heterogeneity. In Figs. 2 and 3, the I2 was
66.1 %, suggesting statistically significant heterogeneity
Fig. 1 The flow diagram of included/excluded studies
between the studies. Accordingly, random-effect models
were utilized.
excluded. Then, three studies were excluded because the
To reduce heterogeneity, data were stratified according
data concerning oral cancer were combined with pharyn-
to source of controls and ethnicity. As shown in Fig. 2, the
geal cancer [13, 14] or combined as head and neck cancer
data were separated into hospital-based and population-
[15]. Lastly, seven case–control studies [16–22] were
based subgroups. The heterogeneity was still evident in the
selected (Fig. 1). All the included seven studies were
hospital-based group (P = 0.043) and population-based
written in English and the genotype distribution of the
(P = 0.029), respectively. However, when data were
controls were consistent with Hardy–Weinberg equilibrium
divided according to ethnicity, we found that the hetero-
in the primary literature.
geneity was significantly reduced or removed in Asian
Of the included studies, three studies were conducted on
group (P = 0.34), Caucasian group (P = 0.165) and
Asians [19, 20, 22], two on Caucasians [16, 18] and two on
Mixed races (P = 0.065), suggesting that ethnicity might
mixed races [17, 21].
be a main reason for the heterogeneity.
We established a database according to the extracted
information from each article. The relevant information
Quantitative data synthesis
was listed in Table 1. According to the lists, the first author
and the number and characteristics of cases and controls for
For slow versus rapid acetylators, the data available for our
each study as well as other necessary information were
meta-analysis were obtained from seven case–control studies
presented.

Table 1 Characteristics of studies included in the meta-analysis

First Publication Number of Number Type of controls Age range (mean), year Country
author year cases (male/ of controls
female) (male/female) Cases Controls

Katoh 1998 40/22 72/50 122 Non-cancerous controls (hospital- NA (61.7) NA (62.4) Japan
based)
Chen 2001 240/101 395/157 552 Community control (population- 18–65 (NA) 18–65 (NA) USA
based)
Hahn 2002 62/32 47/45 92 Healthy blood donors (ethnically- 24–90 (61.5) 19–67 (45.1) Germany
matched; population-based)
Marques 2006 193/38 168/44 212 Controls (Age-,gender-, 23–79 (56.6) 23–79 (56.6) Brazil
skin clor-, matched; hospital-based)
Majumder 2007 198/112 302/87 389 Controls (hospital-based) 25-88 (55) 25-80 (49) India
Buch 2008 154/43 302/114 416 Controls (age-,sex-, zip code-, 23–81 (58.7) 27–84 (58.7) USA
matched; population-based)
Balaji 2012 86/71 46/86 132 Controls (hospital-based) NA (53.08) NA (55.07) India
NA not available

123
8816 Mol Biol Rep (2012) 39:8813–8819

Table 2 Distribution of NAT2 acetylators among oral cancer cases and controls included in the meta-analysis
First author SNP sites studied Genotyping Cases Controls
method
Rapid Slow Rapid Slow

Katoh NAT2*4; *5; *6; *7; *14 PCR-RFLP 55 7 115 7

Chen NAT2*4; *5; *6; *7; *12; *14 PCR-RFLP 143 198 250 302
Hahn NAT2*4; *5; *6; *7; *12; *13; *14 PCR-RFLP 35 59 35 57
Marques NAT2*4; *11 PCR-RFLP 202 29 174 38
Majumder NAT2*4; *5; *6; *7; *12 PCR-RFLP 107 190 137 205
Buch 111T [ C; 190C [ T; 191G [ A; 282C [ T;341T [ C; PCR-RFLP 113 84 192 224
411A [ T; 481C [ T; 590G [ A; 759C [ T; 803A [ G;
845A [ C; 857G [ A; 859T [ C
Balaji 481C [ T; 590G [ A; 857G [ A Taqman 57 100 65 67

Fig. 2 Meta-analysis with a random-effect model for the association of oral cancer risk with NAT2 polymorphism (slow versus rapid; stratified
by control sources). HB hospital-based, PB population-based

of 1,379 cases and 1,868 controls. The overall OR for the slow
versus rapid genotypes was 1.04 (95 % CI = 0.79–1.39)
(Fig. 2). Results suggest that individuals who carry slow
acetylators may not have increased or decreased oral cancer
risk compared with those who have rapid ones.
Considering the possible impact of ethnic variation on
the results, we further conducted subgroup analysis con-
cerning Asian, Caucasian and Mixed races, respectively.
The pooled ORs were 1.38 (95 % CI = 1.04–1.82) in
Asians, 0.76 (95 % CI = 0.48–1.21) in Caucasians and
0.91 (95 % CI = 0.53–1.56) in Mixed races, respectively.
Results suggested that slow acetylators might increase oral
cancer susceptibility among Asians but not Caucasians.
In the subgroup analysis by source of controls, the data
regarding the two groups showed no significant associa-
tions respectively.

123
Mol Biol Rep (2012) 39:8813–8819
Fig. 3 Meta-analysis with a random-effect model for the association of oral cancer risk with NAT2 polymorphism (slow versus rapid; stratified
by ethnicity)
Sensitivity analysis
When the random-effect model was changed as fixed-effect
model, the significance of the overall data was not statis-
tically altered (data not shown). Moreover, we also con-
ducted one-way sensitivity analysis [24] to evaluate the
stability of the meta-analysis. Interestingly, when the study
conducted by Buch et al. [16] was deselected, I2 reduced to
40.0 %, with P value more than 0.1. When the remaining
six studies were deleted respectively, I2 varies from 61.0 to
71.8 %, with P value less than 0.1. However, the statistical
significance of the results was not altered when any single
study (including Buch et al.) was omitted (data not shown),
confirming the stability and credibility of the results.
Bias diagnostics
Funnel plot was created for assessment of possible publi-
cation biases (Fig. 4a). Then, Egger’s linear regression test
was used to assess the symmetry of the plot (Fig. 4b). The
data suggest that the funnel plot was symmetrical
(t = 0.36, P = 0.735), suggesting that the results of these
meta-analyses are relatively stable and the publication
biases may have little influence on the results.
8817
Discussion
In the present study, the results of meta-analyses showed
that individuals with NAT2 polymorphism might have
associations with increased susceptibility to oral cancer
among Asians but not Caucasians.
A previous meta-analysis [25] regarding prostate cancer
suggests that NAT2 polymorphism may increase suscep-
tibility to prostate cancer in Asians. Similarly, another
meta-analysis [26] concerning laryngeal cancer indicates
that slow acetylators may increase laryngeal cancer risk in
Asians. Nevertheless, slow acetylators only increase blad-
der cancer [27, 28] and breast cancer [29, 30] risk for
individuals who have a heavy smoking history. While for
lung [31] and gastric cancer [32], the data failed to show an
evidence of NAT2 polymorphisms increasing cancer risk.
Thus, effects of NAT2 genetic variation varied on diverse
carcinomas.
The underlying mechanisms by which NAT2 polymor-
phism influences cancer risk are not fully understood. The
NAT2 gene is located on chromosome 8p22, encoding a
290-amino-acid protein [33]. NAT2 catalyze the detoxifi-
cation and/or activation of aromatic and heterocyclic amine
carcinogens by two pathways. The metabolism reaction
123
8818
Fig. 4 Publication bias tests (a funnel plot; b Egger’s linear
regression test)
may result in the detoxification by N-acetylation, or bio-
activation by O-acetylation often preceded by CYP450
hydroxylation [6]. Genetic variation of NAT2 may lead to
differences in the rate of arylamine metabolism and con-
sequently cancer risk [34].
Considering that the same polymorphisms may play
different roles in cancer susceptibility among different
ethnic populations and the frequencies of single nucleotide
polymorphisms might be different among different ethnic
groups which might contribute to the possible presence of
heterogeneity between the studies, we stratified the data
according to ethnicity. Consequently, data suggest that
slow acetylators might increase oral cancer risk in Asians
but not Caucasians or Mixed races. The difference might
be owing to the differences of genetic backgrounds and the
environment existed among different races.
Smoking is a commonly accepted risk factor for cancers
and has been thought to interact with gene polymorphism
in oral cancerigenesis [35]. However, insufficient data
regarding smoking and NAT2 genetic variation were
available from the primary literature. Thus, the possible
association could not be evaluated in the present research.
123
Mol Biol Rep (2012) 39:8813–8819
Evident heterogeneity was observed in this study. Thus,
random-effect models were used. To diminish the hetero-
geneity, data were divided according to control sources and
ethnicity, respectively. In control source subgroups, the
heterogeneity still existed, implying that source of controls
was unlikely to be a reason for the heterogeneity. Never-
theless, reduced or removed heterogeneity were observed
when the data were separated by ethnicity, indicating eth-
nicity as a major factor contributing to heterogeneity.
Notably, the study conducted by Buch et al. [16] presented
statistically significant data (OR = 0.64; 95 % CI
0.45–0.90), resulting from a higher difference in the fre-
quencies observed between cases and controls, and an
inversion in the frequency of rapid acetylators compared to
slow acetylators in cases (57.4 and 42.6 %) than in controls
(46.2 and 53.8 %, respectively). The discrepancy might be
due to the limited sample sizes. In the sensitivity analysis,
we found that data from Buch et al. might contribute to the
marked heterogeneity. However, the statistical significance
of the results was not altered when this study was omitted.
Therefore, the study conducted by Buch et al. was not
excluded from the present analyses.
Publication biases were assessed via funnel plot and its
symmetry was further evaluated by Egger’s linear regres-
sion test as shown in Fig. 4. The data of Egger’s test suggest
that publication biases may exert little effect on the results.
Some limitations might be included in this study. First, in
this meta-analysis, most published studies and papers written
in English were searched. Some related published or
unpublished studies that might meet the inclusion criteria
were missed. Therefore, inevitable publication biases might
exist in the results. Second, the data were stratified only by
race and control source, not by age, smoking habit or other
environmental factors because insufficient information could
be extracted from the primary manuscripts. For Asians, only
data regarding Japanese and Indians were included. Further
studies concerning Chinese, Thais and other Asians were
warranted. Third, hospital-based controls were used in sev-
eral included studies. Hence, non-differential misclassifi-
cation bias might exist. Furthermore, the number as well as
the sample sizes of some included studies is rather small, a
number of further studies with large sample sizes are
required. Additionally, gene-gene and gene-environment
interactions should also be considered in the further studies.
In summary, the results of the present meta-analysis
suggest that genetic variations of NAT2 may be a risk
factor for oral carcinoma among Asians.
Acknowledgments This work was supported by Initial Fund for
Doctors of Guiyang Medical College (2009–14) and China Postdoc-
toral Science Foundation (20100471772).
Conflict of interest None declared.
Mol Biol Rep (2012) 39:8813–8819
References
1. Zygogianni AG, Kyrgias G, Karakitsos P, Psyrri A, Kouvaris J
et al (2011) Oral squamous cell cancer: early detection and the
role of alcohol and smoking. Head Neck Oncol 3:2
2. Reichart PA, Nguyen XH (2008) Betel quid chewing, oral cancer
and other oral mucosal diseases in Vietnam: a review. J Oral
Pathol Med 37:511–514
3. Boffetta P (2010) Biomarkers in cancer epidemiology: an inte-
grative approach. Carcinogenesis 31:121–126
4. Klaunig JE, Kamendulis LM, Hocevar BA (2010) Oxidative
stress and oxidative damage in carcinogenesis. Toxicol Pathol
38:96–109
5. Zhuo WL, Zhang YS, Wang Y, Zhuo XL, Zhu B et al (2009)
Association studies of CYP1A1 and GSTM1 polymorphisms with
esophageal cancer risk: evidence-based meta-analyses. Arch Med
Res 40:169–179
6. Liu L, Wagner CR, Hanna PE (2009) Isoform-selective inacti-
vation of human arylamine N-acetyltransferases by reactive
metabolites of carcinogenic arylamines. Chem Res Toxicol
22:1962–1974
7. Garcia-Martin E (2008) Interethnic and intraethnic variability of
NAT2 single nucleotide polymorphisms. Curr Drug Metab
9:487–497
8. Agundez JA (2008) Polymorphisms of human N-acetyltransfer-
ases and cancer risk. Curr Drug Metab 9:520–531
9. Luck H, Kinzig M, Jetter A, Fuhr U, Sorgel F (2009) Mesalazine
pharmacokinetics and NAT2 phenotype. Eur J Clin Pharmacol
65:47–54
10. Sabbagh A, Darlu P, Crouau-Roy B, Poloni ES (2011) Arylamine
N-acetyltransferase 2 (NAT2) genetic diversity and traditional
subsistence: a worldwide population survey. PLoS One 6:e18507
11. Munafo MR, Clark TG, Flint J (2004) Assessing publication bias
in genetic association studies: evidence from a recent meta-
analysis. Psychiatry Res 129:39–44
12. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in
meta-analysis detected by a simple, graphical test. Br Med J
315:629–634
13. Hou YY, Ou HL, Chu ST, Wu PC, Lu PJ et al (2011) NAT2 slow
acetylation haplotypes are associated with the increased risk of
betel quid-related oral and pharyngeal squamous cell carcinoma.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:484–492
14. Jourenkova-Mironova N, Wikman H, Bouchardy C, Mitrunen K,
Dayer P et al (1999) Role of arylamine N-acetyltransferase 1 and
2 (NAT1 and NAT2) genotypes in susceptibility to oral/pharyn-
geal and laryngeal cancers. Pharmacogenetics 9:533–537
15. Morita S, Yano M, Tsujinaka T, Akiyama Y, Taniguchi M et al
(1999) Genetic polymorphisms of drug-metabolizing enzymes
and susceptibility to head-and-neck squamous-cell carcinoma. Int
J Cancer 80:685–688
16. Buch SC, Nazar-Stewart V, Weissfeld JL, Romkes M (2008)
Case–control study of oral and oropharyngeal cancer in whites
and genetic variation in eight metabolic enzymes. Head Neck
30:1139–1147
17. Chen C, Ricks S, Doody DR, Fitzgibbons ED, Porter PL et al
(2001) N-acetyltransferase 2 polymorphisms, cigarette smoking
and alcohol consumption, and oral squamous cell cancer risk.
Carcinogenesis 22:1993–1999
18. Hahn M, Hagedorn G, Kuhlisch E, Schackert HK, Eckelt U
(2002) Genetic polymorphisms of drug-metabolizing enzymes
and susceptibility to oral cavity cancer. Oral Oncol 38:486–490
8819
19. Katoh T, Kaneko S, Boissy R, Watson M, Ikemura K et al (1998)
A pilot study testing the association between N-acetyltransferases
1 and 2 and risk of oral squamous cell carcinoma in Japanese
people. Carcinogenesis 19:1803–1807
20. Majumder M, Sikdar N, Ghosh S, Roy B (2007) Polymorphisms
at XPD and XRCC1 DNA repair loci and increased risk of oral
leukoplakia and cancer among NAT2 slow acetylators. Int J
Cancer 120:2148–2156
21. Marques CF, Koifman S, Koifman RJ, Boffetta P, Brennan P et al
(2006) Influence of CYP1A1, CYP2E1, GSTM3 and NAT2
genetic polymorphisms in oral cancer susceptibility: results from
a case–control study in Rio de Janeiro. Oral Oncol 42:632–637
22. Balaji L, Krishna BS, L VKSB (2011) An unlikely role for the
NAT2 genotypes and haplotypes in the oral cancer of South
Indians. Arch Oral Biol. doi:10.1016/j.archoralbio.2011.10.019
23. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Mea-
suring inconsistency in meta-analyses. Br Med J 327:557–560
24. Tobias A (1999) Assessing the influence of a single study in the
meta-analysis estimate. Stata Techn Bull 8:15–17
25. Gong C, Hu X, Gao Y, Cao Y, Gao F et al (2011) A meta-analysis
of the NAT1 and NAT2 polymorphisms and prostate cancer: a
huge review. Med Oncol 28:365–376
26. Ying XJ, Dong P, Shen B, Wang J, Wang S et al (2011) Possible
association of NAT2 polymorphism with laryngeal cancer risk:
an evidence-based meta-analysis. J Cancer Res Clin Oncol
137:1661–1667
27. Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Ko-
gevinas M et al (2005) NAT2 slow acetylation, GSTM1 null
genotype, and risk of bladder cancer: results from the Spanish
Bladder Cancer Study and meta-analyses. Lancet 366:649–659
28. Moore LE, Baris DR, Figueroa JD, Garcia-Closas M, Karagas
MR et al (2011) GSTM1 null and NAT2 slow acetylation
genotypes, smoking intensity and bladder cancer risk: results
from the New England bladder cancer study and NAT2 meta-
analysis. Carcinogenesis 32:182–189
29. Ochs-Balcom HM, Wiesner G, Elston RC (2007) A meta-analysis
of the association of N-acetyltransferase 2 gene (NAT2) variants
with breast cancer. Am J Epidemiol 166:246–254
30. Zhang J, Qiu LX, Wang ZH, Wang JL, He SS et al (2010) NAT2
polymorphisms combining with smoking associated with breast
cancer susceptibility: a meta-analysis. Breast Cancer Res Treat
123:877–883
31. Cui D, Wang Z, Zhao E, Ma J, Lu W (2011) NAT2 polymor-
phism and lung cancer risk: a meta-analysis. Lung Cancer 73:
153–157
32. Zhong X, Hui C, Xiao-Ling W, Yan L, Na L (2010) NAT2
polymorphism and gastric cancer susceptibility: a meta-analysis.
Arch Med Res 41:275–280
33. Brockton N, Little J, Sharp L, Cotton SC (2000) N-acetyltrans-
ferase polymorphisms and colorectal cancer: a HuGE review. Am
J Epidemiol 151:846–861
34. Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ et al
(2009) Genetic polymorphism in N-acetyltransferase (NAT):
population distribution of NAT1 and NAT2 activity. J Toxicol
Environ Health B Crit Rev 12:440–472
35. de Lima KW, Guembarovski RL, Oda JM, Ramos G, Oliveira BV
et al (2011) Association between the STin2 VNTR polymorphism
and smoking behavior in oral cancer patients and healthy indi-
viduals. Clin Exp Med. doi:10.1007/s10238-011-0140-y
123