Tobacco
smoke produces oxidative and alkylative DNA damage that necessitates repair by base excision repair coordinated by X-ray cross-complementing gene 1 (XRCC1). We investigated whether polymorphisms in XRCC1 alter DNA repair capacity and modify
breast cancer risk associated with smoking. To show the functionality of the 280His variant, we evaluated single-strand break (SSB) repair capacity of isogenic Chinese hamster ovary cells expressing human forms of XRCC1 after exposure to
hydrogen peroxide (H(2)O(2)),
methyl methanesulfonate (MMS), or
camptothecin by monitoring
NAD(P)H. We used data from the Carolina
Breast Cancer Study (CBCS), a population-based, case-control study that included 2,077 cases (786 African Americans and 1,281 Whites) and 1,818 controls (681 African Americans and 1,137 Whites), to examine associations among XRCC1
codon 194, 280, and 399 genotypes,
breast cancer, and smoking. Odds ratios and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression. Only cells expressing the 280His
protein accumulated SSB, indicated by
NAD(P)H depletion, from both H(2)O(2) and MMS exposures. In the CBCS, positive associations were observed between
breast cancer and smoking dose for participants with XRCC1
codon 194
Arg/Arg (P(trend) = 0.046), 399
Arg/Arg (P(trend) = 0.012), and 280
His/His or His/Arg (P(trend) = 0.047) genotypes. The 280His allele was in strong linkage disequilibrium with 194Arg (Lewontin's D' = 1.0) and 399Arg (D' = 1.0). These data suggest that less common, functional polymorphisms may lie within common haplotypes and drive gene-environment interactions.