Although various carcinogenic agents (e.g., ionizing radiation, polycyclic aromatic hydrocarbons, N-nitroso compounds, dietary nitrosamines, organic solvents, unfiltered cigarettes, and pesticides) have been suggested as possible risk factors for brain cancer, none have emerged as dominant factors. The etiology of most of brain tumors continues to be poorly understood (1). A genetically based difference in susceptibility to carcinogens may play a role in the development of glioma.

Few studies have examined the relationship between genetic polymorphisms of metabolizing enzymes and glioma risk. The finding by Trizna et al.(2) of a suggestive, but nonsignificant, elevation in glioma risk for the rapid NAT2acetylator genotype suggested that further exploration of this polymorphism might be worthwhile. If aromatic/heterocyclic amines are associated with gliomas, then functional variations in enzymes that metabolize these carcinogens might modify the risk for glioma among exposed individuals. To evaluate this possibility, we examined NAT2 and NQO1 polymorphisms in conjunction with smoking history in adult glioma cases and controls.

The 159 cases and 163 controls in this study have been described elsewhere (3, 4). DNA samples, obtained from whole blood,were genotyped for NAT2 with a modification of the PCR-RFLP method of Bell et al.(5) that allows classification of individuals as slow versus rapid acetylators. NQO1 has been demonstrated to be polymorphic(C-to-T transition at bp 609), and a 3-fold decrease in reductase activity is associated with this allelic variant. Genotyping for NQO1 used the PCR method described previously by Wiencke et al.(6). Unadjusted ORs3and 95% CIs comparing NAT2 and NQO1 genotypes and smoking histories of white cases and controls were estimated with unconditional logistic regression analyses. Analyses of smoking history were stratified by genotypes. Analyses also were adjusted for subjects’ age and gender.

For NAT2, 63% of cases and 54% of controls had the slow acetylator genotype, but this difference was not significantly different (P > 0.05). Overall, in both unadjusted and adjusted comparisons, cases were somewhat (40–50%, respectively) more likely than controls to have the NAT2 slow acetylator genotype (Table 1). Among subjects with fast acetylator genotypes, cases appeared to be more likely than controls to have smoked unfiltered cigarettes, but these results were not significant, and the CI was very wide(case-control OR for having smoked unfiltered cigarettes versus never smoked, 3.6; 95% CI, 0.4–36.9). The ORs for smoking filtered cigarettes versus never smoking and the ORs for smoking either filtered or unfiltered cigarettes among those subjects with NAT2 slow acetylator genotypes were all very close to 1. Looked at another way, among subjects who never smoked or who smoked filtered cigarettes, cases were somewhat more likely than controls to have slow acetylator genotypes, whereas among subjects who smoked unfiltered cigarettes, cases were less likely than controls to have slow acetylator genotypes. Almost identical percentages of cases(32%) and controls (34%) were heterozygous for the NQO1variant, whereas 4% of both cases and controls were homozygous for this variant. Importantly, all of these findings were compatible with chance.

Statistical Power.

With 54% of controls being NAT2 slow acetylators and 37%of controls being NQO1 variants, we had ∼90% power to detect ∼2-fold ORs. Thus, we cannot entirely rule out the possibility of a modest association of NAT2 slow acetylator genotype and glioma.

Study Limitations.

Although adequate power was available to detect an association between genotype and glioma, power may have been insufficient to detect an interaction between NAT2 and smoking with glioma. In addition, exposure misclassification, selection, and recall bias are concerns in case-control studies and may have influenced the observed results.

In conclusion, these results provide no support for an association of NQO1 variant genotype and glioma. The results also do not support the hypothesis suggested by Trizna et al.(2) that the NAT2 fast acetylator genotype might increase the risk of gliomas. Trizna et al.(2) reported a 1.6-fold (0.84–3.17) elevation in risk for the NAT2 fast acetylator genotype from a case-control study of 90 cases and 90 controls. In our somewhat larger study, we observed the opposite, a 1.4-fold OR of glioma with the NAT2 slow acetylator genotype. Although some of the discrepancy between the two studies may be attributable to variations in genotype frequencies in the control populations, that variation is unlikely to be solely responsible for the magnitude of difference between the two studies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

        
1

This work was supported by National Institute of Environmental Health Sciences Grants P42ES04705, ES00002, and ES06717,National Cancer Institute Grants CA57220 and CA52689, National Institute of Dental Research Grant DE-92-05, and a grant from The Brain Tumor Society.

                
3

The abbreviations used are: OR, odds ratio; CI,confidence interval.

Table 1

Gender, age, smoking history, and NAT2 and NQO1genotypes among white glioma cases and controls in the San Francisco Area Adult Glioma Study, 1991–1995

A. Risk Factor
Genotyped populationa
Case (n = 159)Control (n = 163)
Gender (%)   
Female 39% 46% 
Male 61% 54% 
Age (yr, mean) 48.2 53.4 
Cigarette smoking (%)   
Never 46% 45% 
Former 37% 41% 
Current 14% 14% 
A. Risk Factor
Genotyped populationa
Case (n = 159)Control (n = 163)
Gender (%)   
Female 39% 46% 
Male 61% 54% 
Age (yr, mean) 48.2 53.4 
Cigarette smoking (%)   
Never 46% 45% 
Former 37% 41% 
Current 14% 14% 
B. Genotypeb
CasesControlsOR (95% CI)cORd (95% CI)
n(%)n(%)
NAT2       
Rapid 58 (37) 72 (46) a a 
Slow 98 (63) 83 (54) 1.5 (0.9–2.3) 1.4 (0.9–2.3) 
NQ01       
Wild type 100 (64) 102 (63) a a 
Reduced activity 57 (36) 61 (37) 1.0 (0.6–1.5) 1.0 (0.6–1.6) 
B. Genotypeb
CasesControlsOR (95% CI)cORd (95% CI)
n(%)n(%)
NAT2       
Rapid 58 (37) 72 (46) a a 
Slow 98 (63) 83 (54) 1.5 (0.9–2.3) 1.4 (0.9–2.3) 
NQ01       
Wild type 100 (64) 102 (63) a a 
Reduced activity 57 (36) 61 (37) 1.0 (0.6–1.5) 1.0 (0.6–1.6) 

a Referent group.

b Not every person was genotyped for each polymorphism.

c OR and 95% CI.

d OR and 95% CI adjusted for age,gender, and ever smoking.

We thank Dr. Nancy Mueller for helpful comments on the manuscript.

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