CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study

A.S. Wenzlaff 1, *, M.L. Cote 1, 2, C.H. Bock 1, 2, S.J. Land 1, 3, 4, S.K. Santer 1, D.R. Schwartz 5 and A.G. Schwartz 1, 2

1 Population Studies and Prevention Program, 2 Department of Internal Medicine, 3 Center for Molecular Medicine and Genetics, 4 Molecular Biology and Human Genetics Program and 5 Proteases and Cancer Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA

* To whom correspondence and reprint requests should be addressed. Tel: +1 313 833 0715 ext. 2484; Fax: +1 313 831 7806; Email: wenzlaff{at}med.wayne.edu


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The cytochrome P450 (CYP) superfamily of enzymes catalyse one of the first steps in the metabolism of carcinogens such as polycyclic aromatic hydrocarbons, nitroaromatics and arylamines. Polymorphisms within the CYP1A1 gene have been shown to be associated with lung cancer risk, predominantly among Asian populations. Despite functional evidence of a possible role of CYP1B1 in lung cancer susceptibility, only a few studies have evaluated polymorphisms in this gene in relation to lung cancer susceptibility. This population-based study evaluates polymorphisms in both of these CYP genes within never smokers, most of whom had environmental tobacco smoke (ETS) exposure. Cases (n = 160) were identified through the metropolitan Detroit Surveillance, Epidemiology and End Results program, and age, sex and race-matched population-based controls (n = 181) were identified using random digit dialing. Neither CYP1A1 MspI nor CYP1A1 Ile462Val was associated with lung cancer susceptibility among Caucasians or African-Americans. Among Caucasians, however, CYP1B1 Leu432Val was significantly associated with lung cancer susceptibility odds ratio (OR) for at least one valine allele = 2.87 [95% confidence interval (CI) 1.63–5.07]. Combinations of this Phase I enzyme polymorphism along with selected Phase II enzyme polymorphisms (GSTM1 null, GSTP1 Ile105Val and NQO1 C609T) were evaluated. The combination of CYP1B1 Leu432Val and NQO1 C609T appeared to be associated with the highest risk of lung cancer (OR = 4.14, 95% CI 1.60–10.74), although no combinations differed significantly from the risk associated with CYP1B1 Leu432Val alone. When individuals were stratified by household ETS exposure (yes/no), CYP1B1 Leu432Val alone and in combination with Phase II enzyme polymorphisms was more strongly associated with increased lung cancer susceptibility among those with at least some household ETS exposure. Additional studies will be required to further validate these findings among never smokers and to evaluate the effects of this polymorphism among smoking populations as well.

Abbreviations: CYP, cytochrome P450; ETS, environmental tobacco smoke; GSTM1 null, glutatione S-transferase µ null; GSTP1 Ile105Val, glutathione S-transferase {pi} Ile105Val; NQO1 C609T, NAD(P)H:quinone oxidoreductase 1 C609T; PAH, polycyclic aromatic hydrocarbons; RFLP, restriction fragment length polymorphism


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Several metabolic enzymes are currently under investigation for their possible role in lung cancer susceptibility, including members of the cytochrome P450 (CYP) superfamily. As Phase I enzymes, these enzymes catalyse one of the first steps in the metabolism of carcinogens. This oxidizing step often creates more reactive intermediates that are capable of binding with DNA and causing genetic mutations (1,2). The CYP superfamily of enzymes is thought to be the primary agent involved in oxidizing carcinogens found in tobacco smoke, such as polycyclic aromatic hydrocarbons (PAHs), nitroaromatics and arylamines (3,4).

CYP1A1 polymorphisms were the first of the CYP genes to be associated with lung cancer. Two of the most studied polymorphisms include an MspI cut site in an intron (CYP1A1 MspI) and an isoleucine to valine change in the heme binding region of the enzyme (CYP1A1 Ile462Val). In Asian populations, these polymorphisms have generally been associated with moderate to high increased risk of lung cancer (5,6). These polymorphisms are much less common in Caucasians and African-Americans and only a few studies have found a statistically significant or near statistically significant association with lung cancer (79). Recent analyses of a pooled population, including a report on a subset of Caucasian non-smokers (10), have reported significant associations between CYP1A1 Ile 462Val and CYP1A1 MspI and lung cancer (10,11).

The CYP1B1 enzyme plays a significant role in the oxidation of a variety of carcinogens such as PAHs and arylamines, and is expressed in the lung (12). An amino acid change from leucine to valine at codon 432 (CYP1B1 Leu432Val) has been associated with elevated levels of DNA adducts within white blood cells (13). Recent functional studies have also reported significantly higher levels of CYP1B1 in the peripheral leukocytes of lung cancer patients versus controls (14). Nevertheless, epidemiologic studies of a possible role of this polymorphism and lung cancer have been very limited (1416).

This study utilizes one of the largest collections of never smoking lung cancer patients to evaluate the connection between three CYP polymorphisms, CYP1A1 Ile462Val, CYP1A1 MspI and CYP1B1 Leu432Val and risk of lung cancer in a low tobacco exposure group. It is the first study to evaluate CYP1B1 Leu432Val in a population of never smokers. Recent analyses of this never smoking population have reported increased risk of lung cancer associated with polymorphisms within the Phase II detoxification enzymes (17,18). Therefore, gene–gene interactions with glutathione S-transferase µ null (GSTM1 null), glutathione S-transferase {pi} Ile105Val (GSTP1 Ile105Val) and NAD(P)H:quinone oxidoreductase 1 C609T (NQO1 C609T) were also evaluated.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study subjects
The study population has been described previously (18). Briefly, lifetime never smokers were identified through two population-based case–control studies in metropolitan Detroit. The first study included never smokers newly diagnosed with lung cancer between 1984 and 1987, age 40–84 years (Study 1) and the second study included lung cancer cases under age 50 years, regardless of smoking exposures and newly diagnosed September 15, 1990–September 30, 2004 (Study 2). A greater proportion of controls than cases were lifetime never smokers, so never smoking controls were randomly selected from within each study to match never smoking cases on race, sex, 5-year age group and county of residence. Whenever possible, controls were frequency matched to cases in a 1:1 ratio in Study 1 and 2:1 in Study 2. Never smokers in both studies were defined as individuals smoking <100 cigarettes in their lifetime.

The overall interview response rate was 64.3% for cases. It was not possible to calculate a response rate for controls because eligibility could not be determined in households refusing to answer the eligibility screen. Of those individuals answering the telephone and providing a household census to determine eligibility, 92.7% participated in the study.

Data and biosample collection
Data and biosample collection have been described previously (18). In brief, trained interviewers conducted telephone interviews to collect demographic information, smoking history, health history and lifetime estimates of environmental tobacco smoke (ETS) exposure. If the study subject was unable to participate due to illness or death, an attempt was made to obtain proxy data by interviewing someone familiar with the subject's history. Biological samples were available for 160 cases and 181 controls. Case biospecimens consisted of 13 blood, 5 buccal and 142 tissue block samples. Normal tissue could be extracted from 56 of the blocks, 50 were determined to be mixtures of normal and tumor tissue, and 36 were mostly tumor. Among the controls, 95 blood and 86 buccal samples were available for analysis. A small number of cases and controls could not be genotyped due to a limited amount of DNA available or poor sample quality. Genotypes were available for at least one locus for 159 cases and 179 controls.

Genotyping
DNA was isolated from whole blood with the Genomic DNA Purification System (Gentra Systems, Minneapolis, MN), buccal swabs with the BuccalAmpTM DNA Extraction Kit (Epicentre Technologies, Madison, WI), or paraffin embedded tissue with the QIAamp DNA Mini Kit (Qiagen, Valencia, CA) following the manufacturer's protocol. When multiple samples were obtained from a study participant, DNA extracted from blood was used preferentially, followed by DNA extracted from buccal swabs and then DNA extracted from paraffin blocks.

Genotypes for both CYP1A1 polymorphisms were ascertained using restriction fragment length polymorphism (RFLP) protocols as described by Drakoulis (19). In both instances, products of the enzyme digests were run out on an 8% polyacrylamide gel and visualized by ethidium bromide staining. Sequencing verified a random sample of 5% of the subjects.

CYP1B1 Leu432Val genotyping was performed using a 5'-nuclease assay (TaqMan, Applied Biosystems, Foster City, CA) for all but 13 subjects, for whom no usable sample remained. These 13 individuals had previously been genotyped using an RFLP protocol described by Zheng (20). For the Taqman assay, DNA isolated from buccal cells or from paraffin blocks was pre-amplified in an outer PCR reaction for added sensitivity. The outer reaction was carried out in a 25 µl reaction volume consisting of 2.5 mmol/l MgCl2, 0.5 µmol/l of each of the forward (5'-CACTGCCAACACCTCTGTCTTG-3') and reverse (5'-AAGAATCGAGCTGGATCAAAGTTC-3') primers, 1.25 U AmpliTaq Gold polymerase, and 200 µmol/l each of dATP, dCTP, dGTP and dTTP. The amplification mixture was denatured at 95°C for 10 min followed by 15 cycles of 94°C for 30 s, 60°C for 30 s and 72°C for 30 s, and a final extension at 72°C for 10 min using an Eppendorf Master Cycler Gradient thermocycler (Eppendorf, Westbury, NY). Oligonucleotide primers and probes were designed using Primer Express software (Applied Biosystems). Standard TaqMan conditions using 1x Universal PCR mix (Applied Biosystems), either 25 ng DNA or 2 µl of an outer amplification reaction (DNA isolated from either buccal cells or paraffin blocks), forward (5'-GGCTACCACATTCCCAAGGA-3') and reverse (5'-AAGAATCGAGCTGGATCAAAGTTC-3') primers, and leucine (6FAM-ATGACCCACTGAAGTG-MGBNFQ) and valine (VIC-ATGACCCAGTGAAGTG-MGBNFQ) probes. An Applied Biosystems 7900 was used for the amplification and detection of products. For quality control, 5% of the products were sequenced and 10% were directly repeated. Genotyping for the Phase II enzyme polymorphisms among this never smoking population was completed for previous publications. Methods for determining genotypes for the GSTM1 null and GSTP1 Ile105Val polymorphisms were described in Wenzlaff et al. (18), and methods for genotyping at NQO1 C609T were described in Bock et al. (17).

Statistical analysis
Allele frequencies for each polymorphism were calculated for cases and controls, stratifying by race and tests for Hardy–Weinberg equilibrium among controls were conducted for each polymorphism. Case allele frequencies were compared by tissue type (normal tissue, normal and tumor tissue combined, and tumor only) using {chi}2-tests. {chi}2-tests were also used to evaluate allele frequencies among cases and controls dichotomized by age (<55 versus ≥55). The effect of each CYP variant on lung cancer risk was tested in unconditional logistic regression models, adjusting for age at diagnosis (cases)/interview (controls), race (Caucasian/African-American), sex and years exposed to household ETS. There were no individuals with the Val/Val genotype at CYP1A1 Ile 462Val. Similarly, there were very few individuals with the C/C genotype at the CYP1A1 MspI site and these individuals were therefore combined with the C/T subjects for analysis purposes. Inclusion of ETS exposure at work, education, history of chronic obstructive lung diseases and family history of lung cancer did not alter results in the multivariate models and therefore these variables were not included in the final models. Similarly, interactions between genotypes and years of ETS exposure were not significant and were not included in the final models. Odds ratios (ORs) and 95% confidence intervals (CI) for each genotype were calculated from coefficients in the final models. Analyses were repeated after stratification by race, sex, histology and household ETS levels. Gene–gene interactions between CYP1B1 Leu432Val and GSTM1 null, GSTP1 Ile105Val and NQO1 C609T were also evaluated. To increase study power when conducting these analyses, GSTP1 genotypes were combined so that individuals with at least one valine allele (Ile/Val or Val/Val) were compared with individuals carrying the Ile/Ile genotype. Similarly, NQO1 C609T CT and TT genotypes were grouped for analysis. Individuals who carried no risk alleles at either gene were used as a reference category for testing gene–gene combinations. These subjects were then compared with subjects who had only one of the genes with a risk genotype or both genes with a risk genotype. Power calculations were conducted (21). All statistical analyses were performed using SAS version 8.02.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Case and control demographic information, histology breakdown and corresponding P-values are detailed in Table I. The mean age was 63.2 years for the cases and 54.9 years for the controls (P < 0.0001). This age difference was due to the oversampling of non-smoking controls from Study 2, where the participants were younger. Genotype frequencies between individuals <55 years of age (the mean age of the controls) and ≥55 years of age were compared to insure independence between age and genotype. Genotypes at either of the CYP1A1 polymorphisms or CYP1B1 Leu432Val did not differ significantly by age group among cases or controls (data not shown). Among those reporting ETS exposure, the mean number of years of household ETS exposure was greater in cases (27.9 years) than controls (23.6 years). There were no significant differences in sex or race distributions between cases and controls (P-values 0.14 and 0.60, respectively). Controls were more likely than cases to have finished high school and had significantly higher education levels overall. In this group of lifetime never smokers, adenocarcinoma was the most predominant histological type (55.6%) and squamous cell carcinoma was the second most common histologic type (16.3%).


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Table I. Characteristics of never smoking cases and controls

 
Table II shows allele frequency data, stratified by race. Genotype data were available for the CYP1A1 MspI variant for 156 cases and 179 controls, for CYP1A1 Ile 462Val for 159 cases and 178 controls, and for CYP1B1 Leu432Val for 159 cases and 178 controls. With the exception of CYP1B1 Leu432 Val in Caucasians ({chi}2 = 4.12, P = 0.04), genotype frequencies among Caucasian and African-American controls were found to be in Hardy–Weinberg equilibrium for all loci (data not shown). Only CYP1B1 Leu432Val exhibited significant differences in allele frequencies when comparing Caucasian controls with African-American controls (P < 0.0001). In particular, the Val/Val genotype was much more likely to occur in African-American controls (67%) than Caucasian controls (18%). Allele frequencies were also evaluated by tissue type (normal, normal and tumor mixed, and tumor only) among cases. Tissue type was not significantly associated with CYP1A1 MspI, CYP1A1 Ile462Val or CYP1B1 Leu432Val genotypes (P-values 0.99, 0.22 and 0.12, respectively) (data not shown).


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Table II. Distribution of cytochrome p450 genotypes among never smokers, stratified by race

 
As reported in Table III, neither CYP1A1 MspI nor CYP1A1 Ile462Val was significantly associated with lung cancer in Caucasians or African-Americans. Due to absence of valine alleles in African-American cases, an OR could not be calculated for CYP1A1 Ile462Val. The CYP1B1 Leu432Val variant was significantly associated with lung cancer in never smoking Caucasians. After adjusting for age at diagnosis/interview, sex and years of household ETS exposure, the presence of one valine allele was associated with a >2.5-fold increased risk of lung cancer (OR = 2.71, 95% CI 1.47–5.01) and the valine/valine genotype was associated with a slightly higher risk (OR = 3.16, 95% CI 1.57–6.35). Among African-Americans, CYP1B1 Leu432Val was not associated with lung cancer susceptibility. Stratification of Caucasians by sex revealed that both males and females exhibited an increase in risk of lung cancer (data not shown). Having at least one valine allele at codon 432 of CYP1B1 yielded very similar results among Caucasian adenocarcinoma patients alone (OR = 2.40, 95% CI 1.24–4.65) (data not shown). Because adenocarcinoma comprised the majority of cases, there were too few cases with other histologies for meaningful analyses.


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Table III. Lung cancer risk associated with cytochrome p450 genotypes among never smokers, stratified by race

 
Since polymorphisms within the CYP1A1 gene were rare and CYP1B1 Leu432Val was the only Phase I polymorphism to be associated with lung cancer, only CYP1B1 Leu432Val was evaluated in conjunction with Phase II detoxification enzyme polymorphisms among Caucasians (Table IV). While having one gene with a risk genotype was associated with intermediate increases in risk of lung cancer, having risk genotypes at both CYP1B1 Leu432Val and a Phase II enzyme polymorphism was associated with the highest risks. After adjusting for age at diagnosis/interview, race, sex and years of household ETS exposure, having at least one valine allele at the CYP1B1 Leu432Val site in conjunction with GSTM1 null was associated with a >2.5-fold increase in lung cancer risk (OR = 2.62, 95% CI 1.18–5.81). Risk associated with having at least one valine allele at both the CYP1B1 and GSTP1 sites was higher (OR = 3.21, 95% CI 1.34–7.74). Finally, the NQO1 risk polymorphism, in combination with at least one valine allele at CYP1B1 Leu432Val, was associated with the highest increase in risk of lung cancer (OR = 4.14, 95% CI 1.60–10.74).


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Table IV. Lung cancer risk associated with CYP1B1 Leu432Val in combination with Phase II enzyme polymorphisms among Caucasian never smokers

 
Caucasian never smokers were stratified by the median level of ETS among exposed Caucasian controls (21 ETS years), as well as by any or no ETS exposure (Table V). The Val/Val variant at CYP1B1 Leu432Val was associated with a non-significant increase in risk among individuals reporting no ETS exposure (OR = 3.35, 95% CI 0.88–12.80). Within this small subset of no ETS exposure individuals, CYP1B1 Leu432Val in combination with either the GSTP1 or NQO1 polymorphisms also resulted in non-significant increased risk. Combining individuals who had the Leu/Val or Val/Val genotypes at CYP1B1 Leu432Val resulted in statistically significant increased risks among the 1–21 ETS exposure years group. The combination of the CYP1B1 Leu432Val and the NQO1C609T polymorphisms also resulted in a statistically significant increase among this group. Similar increases in risk in association with CYP1B1 Leu432Val were observed for individuals with ≥22 ETS exposure years, however, the risks associated with CYP1B1 Leu432Val in combination with either GSTM1 null or NQO1C609T were even higher, suggesting a possible ETS dosage effect in those carrying multiple risk genotypes (OR = 6.73, 95% CI 1.40–32.31 and OR = 12.18, 95% CI 1.09–136.76, respectively). Finally, among individuals reporting any ETS exposure, statistically significant increases in risk were associated with either CYP1B1 Leu432Val alone or in combination with any of the Phase II polymorphisms evaluated. In particular, the combination of CYP1B1 Leu432Val and NQO1C609T was associated with the highest increases in risk of lung cancer among individuals reporting any ETS exposure (OR = 7.68, 95% CI 1.97–29.92).


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Table V. Lung cancer risk associated with CYP1B1 Leu432Val alone and in combination with Phase II enzyme polymorphisms among Caucasian never smokers by ETS exposure strata

 
Power calculations were conducted to evaluate our ability to detect possible effects associated with the CYP1A1 polymorphisms among Caucasians and African-Americans. The power to detect a true OR of 1.8 for the CYP1A1 Ile462Val polymorphism in this population of Caucasians was 70%. Combining Caucasians who were C/T or C/C at the CYP1A1 MspI site resulted in 80% power to detect a true OR of 1.9. Among African-Americans, calculations revealed a 60% power to detect an OR of 1.8 for the CYP1A1 MspI polymorphism and <60% power to detect the same OR for the CYP1A1 Ile462Val variant.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The CYP1A1 MspI or CYP1A1 Ile462Val polymorphisms are rare in Caucasians and African-Americans. While studies of African-Americans have reported predominantly negative findings (22,23), studies of Caucasians have been mixed (7,9,24). Among our population of never smokers, no significant associations between either of the CYP1A1 variants were identified. In contrast, a recent pooled analysis by Hung reported >2-fold increases in lung cancer susceptibility for both CYP1A1 MspI (OR = 2.17, 95% CI 1.12–4.12) and CYP1A1 Ile462Val (OR = 2.99, 95% CI 1.51–5.91) among Caucasian non-smokers (10).

Because the frequency of the CYP1B1 variant varied significantly by race, extended analyses included only Caucasians to limit potential bias due to population stratification. Studies have demonstrated that the CYP1B1 enzyme is expressed in the lung (4,12) and appears in significantly higher levels within the peripheral leukocytes of lung cancer patients versus controls (14). Furthermore, rodents without CYP1B1 activity have been reported to be more resistant to dimethylbenz[a]anthracene (a PAH)-induced tumors than rodents with CYP1B1 activity (25). Although CYP1B1 is therefore a plausible candidate for contributing to lung carcinogenesis, we are aware of only three epidemiologic studies that have evaluated a possible association between polymorphisms within this gene and lung cancer. Watanabe et al. (15) reported in 2000 that CYP1B1 Leu432Val genotype frequencies did not differ significantly between lung cancer cases and healthy controls. Results from Wu et al. (14) concurred that CYP1B1 Leu432Val was not associated with lung cancer (OR = 1.41, 95% CI 0.49–4.00), although only 42 lung cancer cases were included in this analysis. While these two studies focused on Asian populations, a recent Danish case-cohort study also reported no association between CYP1B1 Leu432Val and lung cancer susceptibility (16).

Our study is the first to evaluate CYP1B1 Leu432Val in a population of never smokers. Within Caucasian never smokers, having one copy of the valine allele at this position was associated with a >2.5-fold increased risk of lung cancer and two copies with a >3-fold increased risk of lung cancer. This effect was not seen in African-Americans (Table III). Analysis of adenocarcinoma cases only and stratification by sex demonstrated that these groups exhibited similar increases in risk to the total Caucasian population (data not shown).

Recent studies have reported interactions between CYP1A1 and GSTM1, predominantly in Asian populations and particularly among squamous cell carcinoma patients (26,27). Although the numbers of individuals in our study with either CYP1A1 risk polymorphism were too small to be analysed, combinations of CYP1B1 Leu432Val and select Phase II enzymes (GSTM1 null, GSTP1 Ile105Val and NQO1 C609T) were evaluated (Table IV). These combinations resulted in statistically significant increases in lung cancer risk; however, all three risk estimates were similar to that for CYP1B1 Leu432Val alone (Table IV).

CYP1B1 Leu432Val alone and in combination with the Phase II enzyme polymorphisms was also evaluated by ETS exposure strata. Having the Val/Val genotype at CYP1B1 Leu432Val was associated with an increased risk of lung cancer for individuals with or without ETS exposure, although this increase in risk was only statistically significant among those reporting at least some household ETS exposure (Table V, OR = 3.33, 95% CI 1.67–6.66). Combinations of a risk genotype at both CYP1B1 Leu432Val and within one of the Phase II enzyme polymorphisms examined were more strongly associated with lung cancer susceptibility among those reporting at least some household ETS exposure, and appeared highest in the highest ETS exposure group. No other published studies have evaluated CYP1B1 Leu432Val and ETS interaction in lung cancer susceptibility.

Despite the large sample of population-based never smokers included in this study, analyses by race, sex, histology and ETS exposure strata were limited by the number of cases. The power to detect true associations between these polymorphisms and lung cancer susceptibility was therefore limited, particularly among African-Americans. The mean age of the controls was also significantly younger than the cases. Younger controls were more likely to provide a blood sample than older controls, and were oversampled. However, none of the genotype distributions varied by age in either cases or controls, so it is unlikely that this age difference confounded the results. Additionally, age was included in all the multivariate models. Tests for Hardy–Weinberg equilibrium revealed the CYP1B1 polymorphism to be slightly out of equilibrium among the Caucasian controls sampled for frequency matching (P = 0.04). However, this polymorphism was in Hardy–Weinberg equilibrium among all Caucasian never smoking controls available (P = 0.18). We repeated all analyses including all available Caucasian never smoking controls, and the results were similar to those presented using the matched sample of controls. Whenever possible, normal tissue was used for genotyping; however, only tumor tissue was available for thirty-six of the cases included in this study. Tissue type (normal, normal and tumor mixed or tumor only) was not significantly associated with CYP1A1 MspI, CYP1A1 Ile462Val or CYP1B1 Leu432Val genotypes, and therefore was not a likely confounder.

In this evaluation of CYP polymorphisms, only CYP1B1 Leu432Val was associated with lung cancer susceptibility. This is the first study to report an association between CYP1B1 Leu432Val and lung cancer in never smokers. Among this population of never smokers, risks associated with this polymorphism appeared to be greater among individuals reporting at least some household ETS exposure and/or those individuals having at least one valine allele at CYP1B1 Leu432Val in combination with GSTM1 null, GSTP1 Ile105Val or NQO1 C609T. Future analyses will be required to further assess interactions between this polymorphism, smoking and risk of lung cancer.


    Acknowledgments
 
This work was supported by NCI Grant R01-CA60691, Contract N01-CN65064 and Contract N01-PC-35145.

Conflict of Interest Statement: None declared.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received May 4, 2005; revised July 11, 2005; accepted July 19, 2005.





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