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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 878-884, April 2005
© 2005 American Association for Cancer Research

Polymorphisms in XPD Exons 10 and 23 and Bladder Cancer Risk

Matthew B. Schabath1, George L. Delclos3, H. Barton Grossman2, Yunfei Wang1, Seth P. Lerner4, Robert M. Chamberlain1, Margaret R. Spitz1 and Xifeng Wu1

Departments of 1 Epidemiology and 2 Urology, University of Texas M.D. Anderson Cancer Center; 3 University of Texas Houston School of Public Health; and 4 Scott Department of Urology, Baylor College of Medicine and Methodist Hospital, Houston, Texas

Requests for reprints: Xifeng Wu, Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Unit 189, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-0807. E-mail: xwu{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: The nucleotide excision repair gene, xeroderma pigmentosum complementation group D (XPD), has been hypothesized to have a role in cancer risk, but results from prior molecular epidemiologic studies and genotype-phenotype analyses are conflicting.

Materials and Methods: We examined the frequency of the XPD Asp312Asn polymorphism in exon 10 and the XPD Lys751Gln polymorphism in exon 23 in 505 incident bladder cancer cases and 486 healthy controls.

Results: Overall, the XPD exon 10 and 23 genotypes were not associated with bladder cancer risk, after adjusting for age, sex, ethnicity, and smoking status. A gender-specific role was evident that showed an increased risk for women, but not for men, associated with the variant genotypes for both exons. For example, when the exon 23 variant allele genotypes were combined (Lys/Gln + Gln/Gln), there was an increased bladder cancer risk in women [odds ratio (OR), 1.69; 95% confidence interval (95% CI), 1.12-2.58] but not in men (OR, 0.99; 95% CI, 0.79-1.24; Pinteraction = 0.041; OR, 1.62; 95% CI, 1.02-2.58). There was also a gene-smoking interaction that showed the variant alleles for either exon or the combination of both increase the risk of bladder cancer for light and heavy smokers. For exon 23 (Pinteraction = 0.057; OR, 1.21; 95% CI, 0.99-1.47), heavy smokers (≥20 pack-years) who carried the exon 23 variant allele genotypes had an OR of 4.13 (95% CI, 2.53-6.73), whereas heavy smokers with the wild-type genotypes were at lower risk (OR, 3.55; 95% CI, 2.19-5.75). Moderate smokers (1-19 pack-years) with the variant allele genotypes had an OR of 1.54 (95% CI, 0.94-2.53), whereas moderate smokers with the wild-type genotypes had an OR of 1.12 (95% CI, 0.63-1.98).

Conclusions: Although we did not observe main effects associated with the XPD genotypes, these results do suggest the variant allele genotypes were associated with increased bladder cancer risk in women and smokers with statistically significant interactions in the exon 23 polymorphism. Although there is biological plausibility, these novel findings for gender and smoking should be interpreted with caution upon confirmation in larger studies.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cigarette smoking, dietary factors, and occupational exposures have been implicated as environmental risk factors for bladder cancer (1-5). Cigarette smoking increases the overall risk for bladder cancer up to 4-fold (4), and about 50% to 66% of bladder tumors in men and 25% in women are attributed to smoking (1). The wide variety of chemical carcinogens found in cigarette smoke includes polycyclic aromatic hydrocarbons, aromatic amines, and N-nitroso compounds, which can form bulky DNA adducts in the urothelial cells after activation by various metabolic enzymes.

The bulky DNA adducts formed by cigarette smoke carcinogens are repaired, for the most part, by the nucleotide excision repair pathway, a multistep system that is also capable of removing UV-induced pyrimidine dimers, photoproducts, and DNA cross-links (6). The nucleotide excision repair–related gene, xeroderma pigmentosum complementation group D (XPD), encodes an ATP-dependent 5' to 3' helicase enzyme required for the local unwinding of the DNA duplex at the lesion site. Unwinding the DNA helix at the site of the lesion is a necessary step in DNA repair to allow other subunits to excise the damaged region. Because XPD is one of several protein subunits of the transcription factor II-H complex, a polymorphism resulting in structural changes of the XPD subunit could modulate interactions with other subunits and modify activity of the whole complex (7). The two XPD polymorphic loci that have been of particular interest in molecular epidemiology studies are the Asp312Asn polymorphism in exon 10 and the Lys751Gln polymorphism in exon 23 (8). Several groups have also done genotype-phenotype analyses with the XPD polymorphisms and have shown that the variant allele genotypes are associated with adverse phenotypic effects such as increased frequency of tobacco-specific p53 mutations (9), increased DNA adduct levels (10-12), and decreased DNA repair capacity (13-15). However, in contrast, two other studies found evidence that the exon 23 Gln allele protects against DNA damage (16, 17). Furthermore, Seker et al. (18) reported reduced apoptotic response associated with the exon 10 Asp allele.

A number of studies of different ethnic populations have investigated the association between the XPD polymorphisms and cancer risk of various sites (19). To our knowledge, there have been only four published reports on the XPD polymorphisms and bladder cancer risk (12, 20-22). In a case-control study of 124 bladder cancer patients and 85 hospital controls, Matullo et al. (12) showed that the exon 23 polymorphism had no effect on the risk of bladder cancer. Similarly, Shen et al. (20) found no association between the exon 23 polymorphism and bladder cancer risk for 201 male bladder cancer cases and 214 male controls. Stern et al. (21) studied the exon 23 polymorphism in 228 bladder cancer cases and 210 controls and found a small but nonsignificant decrease in risk for the Gln/Gln genotype [odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.4-1.3] compared with subjects with the Lys/Lys or Lys/Gln genotypes. More recently, Sanyal et al. (22) also found no association between bladder cancer and the XPD exon 23 polymorphism in 307 bladder cancer cases and 246 controls.

Several studies have also investigated these polymorphisms for risk of lung cancer. For example, in 341 Caucasian lung cancer cases and 360 controls, Spitz et al. (13) found an OR of 1.51 (95% CI, 0.76-3.00) for exon 10 (Asn/Asn versus Asp/Asp), an OR of 1.36 (95% CI, 0.84-2.20) for exon 23 (Gln/Gln versus Lys/Lys), and an OR of 1.84 (95% CI, 1.11-3.04) for individuals homozygous for both variant genotypes. Zhou et al. (23) studied 1,092 lung cancer cases and 1,240 spouse and friend controls and found an OR of 1.47 (95% CI, 1.1-2.0) for exon 10 (Asn/Asn versus Asp/Asp) and an OR of 1.06 (95% CI, 0.8-1.4) for exon 23 (Gln/Gln versus Lys/Lys). In a study of 96 non–small cell lung cancer cases and 96 healthy controls, individuals with the exon 10 Asp/Asp genotype were found to have almost twice the risk of lung cancer (OR, 1.86; 95% CI, 1.02-3.40) than those with the Asp/Asn and Asn/Asn genotypes combined, whereas no association was found with the exon 23 polymorphism (24). In two separate case-control studies in Chinese populations, elevated lung cancer risks were associated with the variant allele genotypes (25, 26), whereas another study found an increased risk associated with the combination wild-type and heterozygote genotypes of exon 23 (27). Hou et al. (10) studied 185 Swedish lung cancer cases and 162 matched population controls and found that having one or two variant alleles was associated with increased risk for lung cancer among younger (<70 years) never smokers for exon 10 (OR, 2.6; 95% CI, 1.1-6.5) and for exon 23 (OR, 3.2; 95% CI, 1.3-8.0). However, both David-Beabes et al. (28) and Park et al. (29) reported no association between the exon 23 polymorphism and lung cancer risk. In addition, no associations have been reported for either polymorphism and risk of melanoma skin cancer (30) or basal cell skin cancer (31), whereas the exon 23 variant genotypes has been associated with a borderline increased risk (OR, 1.55; 95% CI, 0.96-2.52) for squamous cell carcinoma of the head and neck (32). The results from the molecular epidemiologic studies and genotype-phenotype analyses are somewhat conflicting, and it is evident that the role of the XPD polymorphisms varies because the studies disagree about which allele is the risk allele.

To shed more light on the role of the XPD polymorphisms in bladder cancer, we examined the XPD exon 10 and 23 polymorphisms in an ongoing cancer case-control study. The number of cases and controls in this study exceeds the number of study subjects from any of the four previous case-control studies on bladder cancer (12, 20-22). We hypothesized that the XPD polymorphisms would modulate the risk for bladder cancer.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population. Beginning in July 1999, incident urinary bladder cancer cases were accrued from The University of Texas M.D. Anderson Cancer Center and Methodist Hospital in Houston, TX. All cases were histologically confirmed and previously untreated with chemotherapy or radiotherapy. There were no age, gender, ethnic, or cancer stage restrictions. M.D. Anderson staff interviewers identified bladder cancer cases during a daily review of computerized appointment schedules for the Departments of Urology and Genitourinary Medical Oncology. Each new patient was screened with a brief eligibility questionnaire that assessed prior cancer therapy and willingness to participate in the epidemiologic study. If the patient was willing to participate, the interviewer accompanied the study participant to a private room to conduct the interview.

Healthy control subjects without a history of cancer, except nonmelanoma skin cancer, were recruited from an ongoing collaboration with the Kelsey-Seybold clinics, Houston's largest private multispecialty physician group, which includes a network of 23 clinics and over 300 physicians. The controls were frequency matched to the cases on age (±5 years), sex, and ethnicity. The potential control subjects were first surveyed by using a short questionnaire to elicit willingness to participate in the study and to provide preliminary demographic data for matching. A Kelsey-Seybold staff member provided the questionnaire to each potential control subject during clinical registration. The potential control subjects were contacted by telephone at a later date to confirm their willingness to participate and to schedule an interview appointment at a Kelsey-Seybold clinical site convenient to the participant. A vast majority of the cases and all of the controls reside in Harris County (where Houston is located) and the seven surrounding counties. To date, the response rate for the cases has been over 90%, whereas the response rate for the controls has been ~75%.

Epidemiologic Data. After informed consent was obtained, all study participants completed a 45-minute personal interview that was given by M.D. Anderson staff interviewers. The interview elicited information on demographics and smoking history. The questionnaire consisted of a fixed script and included introductory and transitional statements. All interviewers were trained in the use of probes. At the conclusion of the interview, a 40-mL blood sample was drawn into coded heparinized tubes. All study participants were compensated with a gift certificate to a local retail grocery store. Human subject approval was obtained from the M.D. Anderson and the Kelsey-Seybold institutional review boards, and for this specific analysis, approval was also obtained from The University of Texas Committee for the Protection of Human Subjects.

An individual who had smoked at least 100 cigarettes in his or her lifetime was defined as an ever smoker. Ever smokers include former smokers, current smokers, and recent quitters (those who had quit within the previous year). For the case subjects, a former smoker was a person who had quit smoking at least 1 year before diagnosis. For the control subjects, a former smoker was a person who had quit smoking at least 1 year before the interview.

DNA Isolation. Genomic DNA was isolated from the lymphocytes of the peripheral blood samples. Briefly, blood serum was isolated and removed from the whole blood by centrifugation, leaving only intact WBCs and RBCs. The RBCs were lysed and subsequently removed by centrifugation. The resulting lymphocytes were washed with lysis buffer and then incubated overnight with proteinase-K, SDS, and Tris-EDTA. After the incubation, cellular debris and protein were removed by using saturated NaCl and centrifugation. The supernatant, containing the genomic DNA, was precipitated and washed several times with ethanol. The resulting DNA pellet was dried at room temperature and solubilized in sterile TE buffer. The DNA concentration was standardized by using a spectrophotometer, DNA samples were stored at –20°C, and aliquots for immediate analysis were stored at 4°C.

Genotype Assays. Previously described RFLP-PCR assays were used to amplify the polymorphic regions for XPD exons 10 and 23 (13). For the exon 10 polymorphism (Asp312Asn), the wild-type (Asp/Asp) genotype produced two DNA bands (507 and 244 bp), the variant genotype (Asn/Asn) produced three bands (474, 244, and 33 bp), and the heterozygous genotype (Asp/Asn) produced four bands (507, 474, 244, and 33 bp). For the XPD exon 23 polymorphism (Lys751Gln), the homozygous wild-type genotype (Lys/Lys) produced two DNA bands (290 and 146 bp), the variant genotype (Gln/Gln) produced three DNA bands (227, 146, and 63 bp), and the heterozygous genotype (Lys/Gln) produced four bands (290, 227, 146, and 63 bp). Positive and negative controls were used in each experiment, and 10% of the samples were randomly selected and reanalyzed with 100% concordance.

Statistical Analysis. All statistical analyses were done using the Intercooled Stata 8.0 statistical software package (Stata Co., College Station, TX). The Pearson {chi}2 test was used to test for differences between the cases and the control subjects in the distribution of gender, ethnicity, smoking status, XPD genotypes, and the categorical variables age, and pack-years smoked. Hardy-Weinberg equilibrium for the XPD genotypes was tested by a goodness-of-fit {chi}2 test. The Student's t test was used to test for differences between the case and control subjects for the continuous variables of age and pack-years smoked. ORs and 95% CIs were calculated as an estimate of relative risk. Unconditional multivariate logistic regression was used to control for possible confounding by age, gender, ethnicity, and smoking status, where appropriate, and when examining interactions between the polymorphism and smoking. Interaction was tested using a multiplicative interaction term included in the multivariate model. Joint effects were done using never smokers with the wild-type genotype as the reference group. Cigarette pack-years smoked was classified into two groups, light and heavy, based on the cutoff point of 20 pack-years, which was the median value of pack-years among the controls.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were 505 bladder cancer cases and 486 controls available for this analysis. Approximately 76% of the cases and 72% of the controls were men (Table 1). There was no difference between the cases and the controls in terms of ethnicity and mean age. However, there were significant differences between the cases and controls in terms of smoking status and pack-years smoked. Twenty-three percent of the cases were current smokers compared to only 8.4% of the controls. As expected, the cases had smoked more (mean pack-years = 50.4 ± 30.6 SD) than the controls (mean pack-years = 37.0 ± 30.4; P = 0.017).


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  		Table 1. Host characteristics by case-control status

 
XPD exon 10 genotype data were available on 497 cases and 477 controls and exon 23 genotype data were available for 480 cases and 461 controls (Table 2). The variant genotype (Asn/Asn) and heterozygote (Asp/Asn) genotype for XPD exon 10 were more frequent among cases than the controls, resulting in an Asn allele frequency of 31.2% in cases and 29.3% in controls (Table 2). The exon 10 genotype frequencies were in Hardy-Weinberg equilibrium for the cases (P = 0.264) and borderline for the controls (P = 0.046). Overall, the XPD exon 10 genotypes were not associated with bladder cancer risk. For the exon 23 polymorphism, the variant genotype (Gln/Gln) and heterozygote (Lys/Gln) genotype were also more frequent among cases than the controls, resulting in a Gln allele frequency of 35.8% in cases and 33.6% in controls. The exon 23 genotype frequencies were in Hardy-Weinberg equilibrium for both the cases (P = 0.624) and the controls (P = 0.917). However, the XPD exon 23 genotypes were also not associated with bladder cancer risk. When the exon 10 and exon 23 genotypes were combined, a total of 367 cases and 333 controls were either homozygous dominant (i.e., wild-type genotype) for both exons, heterozygous for both exons, or homozygous recessive (i.e., variant genotype) for both exons. Although the combined exon 10 and 23 variant alleles were more frequent in cases (32.6%) than in controls (29.3%), there was no association with bladder cancer risk. For the gender- and smoking-specific analyses (Tables 3 and 4), the genotypes from both exons were grouped to create four strata of genotypes by combining the wild-type genotypes together, the heterozygote genotypes together, the variant genotypes together, and the combination of heterozygote and variant genotypes.


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  		Table 2. XPD genotypes and bladder cancer risk

 

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  		Table 3. XPD genotypes and bladder cancer risk by gender

 

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  		Table 4. XPD genotypes, pack-years smoked, and bladder cancer risk

 
When the XPD genotypes were analyzed by gender, the variant allele genotypes for exon 10, exon 23, and the combination of both exons were associated with an increased bladder cancer risk for women but not for men (Table 3). When we compared the Asn/Asn genotype versus Asp/Asp for exon 10, the OR for women was 1.72 (95% CI, 1.06-2.77), whereas the OR for men was 1.03 (95% CI, 0.80-1.32; Pinteraction = 0.207; OR, 1.11; 95% CI, 0.85-2.11). Furthermore, the variant allele genotypes (Asp/Asn + Asn/Asn) for exon 10 were associated with a statistically significant increased risk of bladder cancer for women (OR, 1.55; 95% CI, 1.03-2.34) but not for men (OR, 1.10; 95% CI, 0.87-1.37; Pinteraction = 0.207; OR, 1.11; 95% CI, 0.85-2.11). Similar gender-specific risks were observed for exon 23 Lys/Gln + Gln/Gln versus Lys/Lys (Pinteraction = 0.097; OR, 1.57; 95% CI, 0.92-2.69) and for Gln/Gln versus Lys/Lys (Pinteraction = 0.041; OR, 1.62; 95% CI, 1.02-2.58). The risk was 2-fold (OR, 2.01; 95% CI, 1.12-3.62) for women with both the exon 10 (Asn/Asn) and exon 23 (Gln/Gln) variant genotypes, whereas no elevated risk was evident for men (OR, 0.99; 95% CI, 0.72-1.35) who carried the same genotypes (Pinteraction = 0.043; OR, 1.97; 95% CI, 1.02-3.81). For women who possessed any of the variant allele genotypes from both exon 10 and exon 23, there was a 1.8-fold (OR, 1.84; 95% CI, 1.11-3.02) increased risk of bladder cancer, but no increase in risk was evident for men (OR, 1.05; 95% CI, 0.80-1.38; Pinteraction = 0.076; OR, 1.65; 95% CI, 0.95-2.85).

We also investigated whether the XPD genotypes modifies the association between smoking and bladder cancer (Table 4). For these analyses, never smokers (i.e., 0 pack-years) with the wild-type genotype were the reference group. Among both moderate smokers (1-19 pack-years) and heavy smokers (≥ 20 pack-years), individuals with the variant genotype had higher ORs than those with the variant allele genotypes (Pinteraction = 0.164; OR, 1.16; 95% CI, 0.94-1.42). Similar patterns for bladder cancer risk were observed for the exon 23 genotypes (Pinteraction = 0.057; OR, 1.21; 95% CI, 0.99-1.47) and the combination of exon 10 and 23 genotypes (Pinteraction = 0.206; OR, 1.18; 95% CI, 0.91-1.51).

Table 5 lists the results of various case-control studies, sorted by cancer site, which have investigated the association between the XPD polymorphisms and cancer. The OR and 95% CI are listed, if available, for the risk genotype(s) for each specific study. For brevity, not every published case-control study was included.


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  		Table 5. Select case-control studies on the XPD polymorphisms and cancer

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated whether the XPD polymorphic loci Asp312Asn (exon 10) and Lys751Gln (exon 23) affected bladder cancer risk in 505 incident bladder cancer cases and 486 healthy frequency-matched controls. Overall, neither polymorphism had a main effect on bladder cancer risk. No other study has investigated the role of the exon 10 polymorphism in bladder cancer risk, whereas four studies (12, 20-22) have investigated the exon 23 polymorphism, and all reported that the exon 23 polymorphism had no overall main effect on the risk of bladder cancer. Both polymorphisms have been extensively studied in several other cancers; however, the findings have not been consistent (Table 5 and reviewed in ref. 19).

Although the XPD exon 10 and 23 polymorphisms did not have an overall effect on bladder cancer risk, there was evidence of a possible gender-specific effect. Among the cases, the frequency of the variant allele genotype for either exon tended to be slightly higher in women than men, yet the frequency among controls was much lower in women compared with men. However, this difference among controls is not statistically significant. We have no explanation for this observation, but several studies have provided evidence that there might be biological plausibility for gender differences in DNA repair capacity. For example, Mayer et al. (33) reported a decrease in double-strand break repair in women compared with men. Similarly, Duval et al. (34) showed a decrease in mismatch repair capacity and increased microsatellite instability for women compared with men. In addition, findings from Kovtun et al. (35) suggest the possibility that X- or Y-encoded factors influence repair or replication of DNA in the embryo. Although, it is possible that our findings occurred by chance alone because the gender-specific effect is essentially driven by differences in genotype frequencies among controls rather than among cases, but these results may also suggest a susceptibility locus because the frequency of the XPD variant genotype differs between healthy women and women with bladder cancer. Thus, women with one or more variant allele genotypes for either exon 10 or 23 were at a significantly increased risk for bladder cancer, and there was a 2-fold increased risk for those women who were homozygous for both the exon 10 and 23 variant genotypes. In support of our findings, several molecular epidemiology studies have reported decreased DNA repair capacity for women compared with men. Castelao et al. (36) suggested that the risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes, because when comparable amounts of cigarettes were smoked, women had higher levels of 3- and 4-aminobiphenyl-hemoglobin adducts than men, suggesting that the higher bladder risk for women may be due to genetic predisposition factors such as reduced DNA repair capacity. Spitz et al. (37) recently reported that DNA repair capacity is significantly lower in women than men for both lung cancer cases and healthy controls. Furthermore, Wei et al. (38) showed that women have lower DNA repair capacity than men and tend to have a much higher risk of basal cell carcinoma skin cancer if they also have a history of sunburns. Other studies have also shown statistically significant higher levels of polycyclic aromatic hydrocarbon adducts in the lung tissue of women than in men, after adjustment for either cumulative lifetime pack-years of smoking or the number of cigarettes smoked per day (39, 40). Overall, these studies suggest that women may have poorer DNA repair capacity than men, which could explain their increased risk of bladder cancer associated with the XPD variant genotypes in our study.

We did not consider smoking in the main effects models, which may partly explain the overall lack of an association between the XPD genotypes and bladder cancer. One would predict an association with the XPD genotypes among individuals who smoke compared with those who do not, because many tobacco carcinogens or their metabolites induce bulky adducts that require DNA repair through the nucleotide excision repair pathway. As expected, moderate to large main effects were observed for light (OR, 1.7) and heavy smokers (OR, 4.0). Indeed, smoking is driving the risk estimates for each level of smoking in the joint effects analysis, but the XPD genotypes do seem to modify the effects within each level of smoking. When the XPD genotypes were analyzed jointly with pack-years smoked, the variant allele genotypes for both exons were associated with higher risks among light and heavy smokers, compared with the wild-type genotypes. In fact, the effect modification was greater than additive and the interaction term was borderline significant for exon 23 (Pinteraction = 0.057; OR, 1.21; 95% CI, 0.99-1.47) suggesting the large independent effects of smoking are further modified by the small independent effects of the XPD genotypes. Matullo et al. (12) and Shen et al. (20) found evidence of a gene-smoking interaction for bladder cancer by smoking status. Matullo et al. (12) reported an OR of 2.53 (95% CI, 0.92-6.96) for current smokers with the exon 23 Gln allele genotypes, and Shen et al. (20) found an increased risk for ever smokers with the exon 23 variant allele genotypes (OR, 4.05; 95% CI, 1.29-12.72), but there was no evidence of a multiplicative interaction (P = 0.80). In the present study, when the genotypes from either exon 10 or 23 were analyzed by smoking status, joint effects were evident in former and ever smokers but not in current smokers (data not shown). However, when the genotypes from exons 10 and 23 were combined, nearly an 8-fold increased risk (OR, 7.97; 95% CI, 3.66-14.35) was observed for current smokers with the variant allele genotypes compared with individuals with the wild-type genotypes (OR, 6.67; 95% CI, 3.03-14.70). Among former smokers, the ORs were 2.85 (95% CI, 1.56-4.27) for individuals with the variant allele genotypes and 1.78 (95% CI, 1.08-2.95) for individuals with the wild-type genotypes (Pinteraction = 0.101; OR, 1.22; 95% CI, 0.96-1.55). In contrast, Stern et al. (21) found no evidence of a gene-smoking interaction with the exon 23 genotypes (Lys/Lys versus Lys/Gln or Gln/Gln) because an OR of 0.8 (95% CI, 0.4-1.9) was found for never smokers and an OR of 1.0 (95% CI, 0.6-1.6) for ever smokers. Although there is evidence of a gene-smoking interaction in bladder cancer, the role of the XPD genotypes in the interaction is not clear because the findings are conflicting.

The functional effect of the XPD polymorphisms remains unclear, although some studies support a deleterious effect of the variant genotypes on DNA repair capacity. For example, Spitz et al. (13) showed that lung cancer cases homozygous for the variant allele in either exon have a significantly reduced capacity for repair of BPDE-induced DNA damage. Because BPDE is a tobacco smoke metabolic product, this observation also supports our hypothesis that a gene-smoking interaction is more likely seen among individuals who smoke compared with those who do not, because cigarette smoking produces various types of DNA damage that requires DNA repair. Similarly, Qiao et al. (14) reported that individuals having the variant XPD genotype from either or both exons had suboptimal DNA repair capacity for UV radiation–induced damage as well. Hou et al. (9) reported that the XPD variant alleles were associated with an increased frequency of tobacco-specific p53 mutations in lung tumors. Hemminki et al. (15) showed that individuals with variant alleles in both XPD exons exhibited decreased repair of cyclobutane dimers after solar irradiation in human skin in situ. Hou et al. (10) found a significantly increased level of aromatic DNA adducts in lung cancer patients and controls homozygous for the XPD variant alleles. The exon 23 Gln allele has also been associated with increased DNA adduct levels in traffic workers (11) and in never smokers (12). Clearly, the role of the XPD polymorphisms on cancer risk is unclear (Table 5) because the findings from epidemiologic analyses are inconsistent.

Limitations of this analysis should be addressed. With a sample size of 505 cases and 486 controls, we have statistical power, with 90% power at the two-sided significance level of 5%, to evaluate moderate main effects (OR ≥ 1.70), yet this sample size is underpowered to evaluate smaller main effects (OR < 1.70). Furthermore, although this sample size is underpowered to assess formal tests of interaction, it is still reasonable to examine joint effects. We opted to provide the results from the tests for statistical interaction because there is evidence of such effects in the exon 23 polymorphism. Limited sample size did prohibit tests for three-way interactions, which would have made it possible to determine if one interaction is driving the other or if both interactions are present simultaneously. Although there is biological plausibility, these novel findings for gender and smoking should be interpreted with caution upon confirmation in larger studies.

In summary, our data are consistent with four previous case-control studies (12, 20-22) which all found no main effects for the XPD polymorphisms and bladder cancer risk. However, the variant allele genotypes in the present study were associated with increased bladder cancer risk in women and smokers with significant interactions with the exon 23 polymorphism.


   Acknowledgments
 
We thank Dr. Maureen E. Goode for editorial assistance.


   Footnotes
 
Grant support: National Cancer Institute grants CA 74880, CA 91846, and CA 86390 and National Cancer Institute cancer prevention fellowship grant R25 CA 57730 (M.B. Schabath).

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.

Received 3/25/04; revised 12/16/04; accepted 1/ 3/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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