XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair
protein that plays a central role in the repair of
DNA strand breaks and base damage from a variety of endogenous and exogenous
oxidants including tobacco
smoke. One genetic polymorphism (G-->A,
Arg-->Gln at
codon 399) occurs within a
poly(ADP-ribose) polymerase binding region and within the central
breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1. The variant 399Gln allele of XRCC1 has been associated with elevated
biomarkers of DNA damage in human cells. We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic
DNA, and questionnaire information from 309 cases of pancreatic
adenocarcinoma and 964 controls that were part of a population-based, case-control study conducted in the San Francisco Bay Area between 1994 and 2001. We genotyped individuals using a mass spectrometry-based method. Because smoking and
obesity are known and suspected
pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (
ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m(2)). We also assessed potential gene-gene interactions between polymorphisms in XRCC1 and
CYP1A1, GSTT1, and GSTM1. We found little or no evidence for an association between XRCC1 genotype and
pancreatic cancer among Caucasians, African-Americans, or Asians. There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men. Relative to never active or passive smokers with the
Arg/Arg genotype, the age- and race-adjusted
ORs and ICRs (95% confidence limits) for heavy smoking (>or=41 pack-years) were: for Gln/Gln or
Arg/Gln genotypes [women OR = 7.0 (2.4, 21), ICR = 3.1 (0.03, 6.2); men OR = 2.4 (1.1, 5.0), ICR = 1.3 (-0.20, 2.8)]; and for the
Arg/Arg genotype [women OR = 2.2 (0.73, 6.4); men OR = 1.5 (0.68, 3.2)]. Analyses of combined genotypes suggested an interaction between XRCC1 (Gln/Gln or
Arg/Gln) and GSTT1/GSTM1-null/null among women but not among men. There was no evidence of interaction between XRCC1 genotype and body mass index. Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced
pancreatic cancer. Our findings, including stronger associations and interactions among women, require replication in additional study populations.