Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients

Sequence variations have been identified in a number of DNA repair genes, i ncluding XPD, but the effect of these polymorphisms on DNA repair capacity (DRC) is uncertain. We therefore examined XPD polymorphisms at Lys751Glu an d Asp312Asn in 341 white lung cancer cases and 360 age-, sex-, ethnicity-, and smoking-matched controls accrued in a hospital-based molecular epidemio logical study of susceptibility markers for lung cancer. As previously repo rted, DRC was statistically significantly lower in the cases than in the co ntrols (7.8% versus 9.5%; P < 0.001), which represents an average 18% reduc tion among the cases. The variant Lys75IGln and Asp312Asn allele frequencie s mere 0.36 and 0.29, respectively, for the cases and 0.33 and 0.27, respec tively, for the controls. For subjects homozygous for the variant genotype at either locus, the adjusted odds ratio [95% confidence interval (CI)I was 1.84 (1.11-3.04; P = 0.018, for trend). Both cases and controls with the w ild-type genotypes exhibited the most proficient DRC. The risk (95% CI) for suboptimal DRC (defined as less than the median DRC value among the contro ls) was 1.57 (0.74-3.35) for those with the Gln/Gln751 genotype. For cases with the Asn/Asn312 genotype, the risk (95% CI) was 3.50 (1.06-11.59). For cases who were homozygous at either locus, the risk was 2.29 (1.03-5.12; P = 0.048, for trend). The pattern was less evident among the controls, altho ugh there was a nonsignificant 41% increase in the risk of suboptimal DRC f or controls who were homozygous at either locus. These results suggest that the two XPD polymorphisms have a modulating effect on DRC, especially in t he cases.