Polymorphisms in XPD Exons 10 and 23 and Bladder Cancer Risk

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Abstract
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.