Cigarette smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD); however there is considerable variation in response to smoke exposure,1 and only 20%-30% of chronic smokers may develop severe impairment of lung function, which is associated with COPD.2 This variation has been suggested to be due to genetic factors and gene-environment interactions to the development of COPD.3 Airway cell DNA damage induced by cigarette smoking4,5 results in the development of COPD, and if it is not effectively repaired, the resultant cell apoptosis and death6 further affect the integrity and local resistance of the airway.7 Indeed, lung cancer patients may have a lower capacity of DNA repair than healthy subjects, and this may modulate the risk of lung cancer associated with smoking.8-10 These facts lead to a major hypothesis that smokers with a reduced repair capacity will be at a higher risk of COPD.
Various kinds of DNA modifications which are induced by a variety of genotoxic compounds in tobacco smoke can be repaired through different pathways,11,12 of which base excision repair (BER) removes certain incorrect and damaged bases to ensure the integrity of the genome.5 8-oxoG DNA glycosylase 1 (OGG1) and DNA repair enzyme X-ray repair cross-complementing group 1 (XRCC1) play a central role in the DNA BER pathway. OGG1 catalyzes the removal of 8-hydrodeoxyguanine (8-OHdG), which has been considered as a key biomarker of oxidative DNA damage.13 The substitution of cysteine for serine at codon 326 (Ser326Cys) is associated with a significant reduction in the repair capacity.14 XRCC1, a base excision repair protein that plays a central role in the BER pathway, has multiple roles in repairing ROS-mediated, basal DNA damage and single-strand DNA breaks.15 More than 60 validated single nucleotide polymorphisms in XRCC1 are listed in the Ensembl database. One of them is the codon 399 polymorphism (Arg399Gln), which is located in the BRCT-1 domain, and is associated with a significant reduction in the repair capacity.16 Some studies have found that hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms are associated with a high risk of lung cancer,17-22 but the effect on the risk of COPD is understudied. In the present hospital-based case-control study, we investigated the association between polymorphisms in DNA repair genes hOGG1 (Ser326Cys) and XRCC1 (Arg399Gln), alone or in combination, and susceptibility of COPD as well as the association by assessment of smoking status and smoking exposure.
Two hundred and one eligible COPD patients were recruited from the Department of Respiratory Medicine of Tongji Hospital between December 2005 and June 2007. COPD was diagnosed in patients who had dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease and confirmed by spirometry (a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC)<0.70).23
Patients were excluded if they had bronchiectasis, tuberculosis or other confounding inflammatory diseases such as malignancy, arthritis, connective tissue disorder or inflammatory bowel disease. Three hundred and nine patients without COPD recruited from the Medical Examination Center of Tongji Hospital during the same period served as controls. They were confirmed to be free from COPD and non-tobacco-related diseases but were frequency-matched by age. All patients were unrelated Han nationality Chinese, born and living in Wuhan, China. The patients and controls were subjected to an interview during which they completed a questionnaire and were subjected to blood sampling. The questionnaire contained information about demographic variables including sex, date of birth, and education level; medical history; family history of cancer; history of tobacco consumption including frequency, duration, and status; and occupational history. Smoking status at the interview was classified into three categories: never smokers (individuals who had never smoked or had smoked for less than 1 year), former smokers (those who stopped smoking 1 or more years before the interview), and current smokers (those who currently smoked or stopped smoking less than 1 year prior to the interview). The cumulative amount of smoking, which was defined as pack-years which were calculated by multiplying the number of packs of cigarettes smoked per day by the number of years smoked, was classified into two subgroups, light and heavy, according to the median pack-years level among the controls.24
This study was approved by the Medical Ethics Committee of Tongji Hospital Affiliated to Tongji Medical College, and informed consent was obtained from all participants.
Five milliliters of venous blood were drawn into heparinized venoject tubes (Jinxin, Hubei, China). DNA was extracted from blood using a commercial kit (Blood Genomic DNA Purification Kit; TIANGEN Biotech CO., Beijing, China).
hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms
PCR-restriction fragment length polymorphism (PCR-RFLP) assay was used to determine the hOGG1 Ser326Cys and XRCC1 Arg399Gln genotypes. PCR primers for hOGG1 (F: 5′-TTGCCTTCGGCCCTGTT-CCCCAAGGA-3′; R: 5′-TTGCTGGTGGCTCCTGAGCCATGGCC-3′) generated a 168 bp fragment. PCR primers for XRCC1 (F: 5′-TCTCTCACTCGCTTTCTTTC-3′; R: 5′-TCTCAGTAGTCTGCTGGCTC-3′) generated a 471 bp fragment. PCR reaction mixture (50 μl) consisted of 100 ng of genomic DNA, 25 pmol of each primer, and 25 μl 2×Taq PCR buffer MasterMix (TIANGEN Biotech CO., Beijing, China). PCR program for hOGG1 was initiated by a 5-minute denaturation step at 94°C, followed by 35 cycles at 94°C for 40 seconds, 65.5°C for 40 seconds, 72°C for 35 seconds, and a final elongation step at 72°C for 10 minutes. PCR program for XRCC1 was initiated by a 5-minute denaturation step at 95°C, followed by 35 cycles at 95°C for 30 seconds, 58.5°C for 30 seconds, 72°C for 30 seconds, and a final elongation step at 72°C for 10 minutes. The 10 μl PCR product was digested overnight with 6 units of Msp I (Takara Biotech Co., Dalian, China) at 37°C for 4 hours. The digestion product was then resolved on 2.0% agarose gel. The homozygous Ser allele (Ser/Ser) was determined by the presence of two bands at 142 bp and 26 bp (too small to be seen); the homozygous Cys allele (Cys/Cys) was determined by the presence of the uncut 168 bp band (indicative of absence of the Msp I cutting site); and the heterozygous Ser/Cys allele was determined by the presence of three bands at 168 bp, 142 bp, and 26 bp (Figure A). The homozygous Arg allele (Arg/Arg) was determined by the presence of two bands at 335 bp and 136 bp; the homozygous Gln allele (Gln/Gln) was determined by the presence of the uncut 471 bp band (indicative of absence of the Msp I cutting site); and the heterozygous Arg/Gln allele was determined by the presence of three bands at 471 bp, 335 bp, and 136 bp (Figure B). The genotyping procedures were validated by randomly selecting 5% of the samples and subjecting them to repeat analysis until 100% concordance was achieved.
Demographic data were presented as means ± standard deviation. The Mann-Whitney U test was used to compare the means and the chi-square test to compare the proportions of categorical variables in the patients and controls. The distributions of genotypes for each polymorphic site were tested to match the Hardy-Weinberg heredity equilibrium by the chi-square test. The cumulative life-time smoking was classified into two subgroups, light and heavy, with a cutoff point of 33, according to the median pack-years level among the controls. The odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by unconditional Logistic regression analysis with adjustment for age, sex, smoking status and smoking exposure. For analysis of combined effect of hOGG1 and XRCC1 genotypes, three categories, 0-1, 2, and 3-4 of alleles, were defined according to the number of allele (hOGG1 326Cys and XRCC1 399Gln) in the hOGG1 and XRCC1 genotypes. All data analyses were performed using Statistical Package for Social Sciences software (SPSS for Windows, version 13.0). A P value < 0.05 was considered statistically significant.
General clinical data
As shown in Table 1, we analyzed the 201 patients and 309 controls. Because of frequency-matching by sex and age, there were no significant differences in sex distribution and age between the patients (male, 69.2%; mean age (65 ± 11) years) and controls (male, 69.3%, mean age (64 ± 11) years) (P>0.05). There were more current smokers in the patients (47.8%) than in the controls (30.7%) (P=0.000). In addition, there were more heavy smokers (33 or more of pack-years of smoking) in the patients (50.7%) than in the controls (34.6%) in smokers (P=0.000).
Hardy-Weinberg equilibrium test
The results of the Hardy-Weinberg equilibrium test for hOGG1 and XRCC1 genotypes are shown in Table 2. The hOGG1 326Cys allele frequencies for the controls and patients were 0.54 and 0.62, and the genotype distribution in the controls was consistent with the Hardy-Weinberg equilibrium law (P>0.05). The XRCC1 399Gln frequencies for the controls and patients were 0.25 and 0.30, and the genotype distribution in the controls was in accord with the Hardy-Weinberg equilibrium law (P>0.05).
Association between hOGG1 and XRCC1 genotypes and COPD risk
The associations between hOGG1 and XRCC1 genotypes and COPD risk are shown in Table 2. There was a significant difference in the hOGG1 Ser326Cys genotypic frequencies between the COPD patients and controls (P=0.004). Compared with the hOGG1 Ser/Ser genotype, no significant association was observed between Ser/Cys and Cys/Cys genotypes and COPD risk. There was no significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls (P>0.05). Compared with the XRCC1 Arg/Arg genotype, individuals carrying the Arg/Gln genotype had a 1.55-fold increase in risk of COPD (95% CI 1.05-2.29, P=0.029), whereas no significant increase in risk was associated with the Gln/Gln genotype.
Association between hOGG1 genotype and COPD risk assessed by smoking status and smoking exposure
Assessment of smoking status revealed that there was a significant difference in the hOGG1 Ser326Cys genotypic frequencies between the COPD patients and controls in current smokers (P=0.000). Compared those with Ser/Ser genotype, the patients in current smokers with Cys/Cys genotype had a significantly increased risk of COPD (adjusted OR=5.07, 95% CI 1.84-13.95, P=0.002), but no significant difference in the hOGG1 Ser326Cys genotypic frequencies between the COPD patients and controls in never and former smokers (P>0.05) (Table 3). Assessment of smoking exposure (33 pack-years) showed that there was a significant difference in the hOGG1 Ser326Cys genotypic frequencies between the COPD patients and controls in light smokers (P=0.025), and compared with those with Ser/Ser genotype, the patients in light smokers with Cys/Cys genotype had a significantly increased risk of COPD (adjusted OR=4.20, 95% CI 1.05-16.80, P=0.042). In heavy smokers, however, no significant association was found between Cys/Cys genotype and COPD risk (P>0.05) (Table 4) although there was a significant difference in the hOGG1 Ser326Cys genotypic frequencies between the COPD patients and controls.
Association between XRCC1 genotype and COPD risk assessed by smoking status and smoking exposure
Assessment of smoking status revealed that there was a significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls in current smokers (P=0.003). Compared with those with XRCC1 Arg/Arg genotype, the patients in current smokers with Arg/Gln genotype had a significantly increased risk of COPD (adjusted OR=2.77, 95% CI 1.52-5.27, P=0.001), but it was not associated with Gln/Gln genotype. There was no significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls in never and former smokers (P>0.05) (Table 3). Assessment of smoking exposure (33 pack-years) revealed that there was a significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls in light smokers (P=0.044). Compared with those with XRCC1 Arg/Arg genotype, the patients in light smokers with Gln/Gln genotype had a significantly increased risk of COPD (adjusted OR= 4.48, 95% CI 1.35-14.90, P=0.014). There was a significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls in heavy smokers (P=0.000). Compared with those with XRCC1 Arg/Arg genotype, the patients in heavy smokers with Arg/Gln genotype had a significantly increased risk of COPD (adjusted OR=2.55, 95% CI 1.42-4.58, P=0.002), but it was not associated with Gln/Gln genotype (Table 4).
Association between combination with hOGG1 and XRCC1 genotypes and COPD risk
There was a significant difference in the 0-1 allele, 2 alleles and 3-4 alleles frequencies between the COPD patients and controls (P=0.000). Compared with those with 0-1 allele, the individuals carrying 3-4 alleles had a significantly increased risk of COPD (adjusted OÆ=3.18, 95% CI 1.86-5.43, P=0.000), but it was not associated with 2 alleles (Table 2). Assessment of smoking status showed that there was a significant difference in the 0-1 allele, 2 alleles and 3-4 alleles frequencies between the COPD patients and controls in current smokers (P=0.000). Compared with those with 0-1 allele, the individuals carrying 3-4 alleles had a significantly increased risk of COPD (adjusted OR=8.32, 95% CI 3.59-19.27, P=0.000), but there was no significant difference in the 0-1 allele, 2 alleles and 3-4 alleles frequencies between the COPD patients and controls (P>0.05) in never and former smokers (Table 3). Assessment of smoking exposure (33 pack-years) demonstrated that there was a significant difference in the XRCC1 Arg399Gln genotypic frequencies between the COPD patients and controls in light/heavy smokers (P=0.000, P=0.003, respectively). Compared with those with 0-1 allele, the individuals carrying 3-4 alleles had a significantly increased risk of COPD (adjusted OR=5.46, 95% CI 2.06-14.42, P=0.002 for light smokers; adjusted OR=2.93, 95% CI 1.43-6.02, P=0.003 for heavy smokers, respectively) (Table 4).
COPD is characterized by airflow obstruction that is not fully reversible. It is a major cause of morbidity and mortality worldwide and its prevalence is still increasing.25 Cigarette smoke is a risk factor for COPD, but only part of smokers develop COPD and cluster in families, suggesting that genetic susceptibility plays a role in the development of COPD.26 Airway cell DNA damage due to cigarette smoking4,5 causes the development of COPD. If it is not effectively repaired, it may lead to cell apoptosis and death6 and further affect the integrity and local resistance of the airway.7 In humans, complex DNA repair systems defend against the consequences of DNA damage and safeguard the integrity of the genome. OGG1 and XRCC1 play a central role in the DNA BER pathway. Although there was no association between OGG1 genotypes and the enzyme activity of OGG1,27,28 Kohno et al14 found that 326Ser-containing OGG1 has a seven-fold higher activity in repairing 8-OHdG than 326Cys-containing OGG1 using a complementation assay of an Escherichia coli mutant. The most striking feature of XRCC1 is its ability to interact with other DNA repair proteins although it has no enzymatic activity.29-31 The Gln allele of XRCC1 Arg399Gln polymorphism is associated with higher levels of DNA adducts32,33 and higher sister chromatid exchange frequencies.16,34 Thus we investigated the association between polymorphisms in DNA repair genes hOGG1 (Ser326Cys) and XRCC1 (Arg399Gln), alone or in combination, and susceptibility of COPD.
In the present study, the allele frequency in the controls with hOGG1 codon 326 Cys (0.54) was similar to that in two other Chinese populations21,35 in contrast to that in Caucasians (0.13 to 0.22).18,36,37 The frequency in the controls with XRCC1 399Gln (0.25) was similar to that in other Chinese populations,38,39 but significantly lower than that in a Caucasian population (0.34).22 The differences in allele frequencies detected in these studies might be due to ethnic variation, heterogeneity of study populations, and different sample sizes.
We observed increased risk of COPD among current/light smokers carrying hOGG1 Cys/Cys genotype, which was consistent with the experimental evidence that the hOGG1 isoform encoded by the Cys allele exhibits decreased base excision repair activity.14,40 Some studies found that hOGG1 Cys/Cys genotype was associated with adenocarcinoma and squamous cell carcinoma, being more evident in the latter.18,21,41 Among current/heavy smokers carrying XRCC1 Arg/Gln genotype there was an increased risk of COPD. This finding was consistent with that XRCC1 399Gln is the at-risk allele demonstrated by genotype-phenotype studies.16,32,34,42,43 Interestingly the association was not found between Gln/Gln genotype and COPD risk in current/heavy smokers but in light smokers. There were three reasons. First, the sample size was not large enough to detect the difference. Second, there were other polymorphisms in XRCC1 such as Arg194Trp and Arg280His, which also influenced the XRCC1 repair capacity,34,44,45 and then the risk for COPD. Third, other repair pathways influenced the risk for COPD. Likely, the reasons can also explain why significant association was found between hOGG1 Cys/Cys genotype and COPD risk in light smokers not in heavy smokers. Another polymorphism in hOGG1 was a G to T transition at position -18, which was also shown to be associated with a 3-fold increased risk of adenocarcinoma of the lung (95% CI: 1.3-7.8).46 Assessment of smoking status showed a significant relationship between hOGG1 Cys/Cys and XRCC1 Arg/Gln genotypes and COPD risk in current smokers but former smokers. Possibly, after quitting smoking, the repair capacity of the body recovered with the reduction of repair capacity of hOGG1 and XRCC1 from hOGG1 Cys/Cys and XRCC1 Arg/Gln genotypes. This finding suggests that quitting smoking plays an important role in reducing the risk of COPD. We also found that individuals with 3-4 alleles were at increased risk of COPD. Hence hOGG1 and XRCC1 are suggested to exert combined effect on the development of COPD, and XRCC1 coordinates and stimulates the hOGG1 activity.47 These results also suggest that individuals with more than one of the at-risk polymorphisms may have a greater risk for developing COPD.
The present study has two limitations. First, the exact biological mechanisms for gene-smoking interaction associations were unclear, because no direct phenotype data were available for the function of these polymorphisms. Hence additional studies are needed to detect the function of these polymorphisms and their associations with COPD risk. Second, we only studied hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms and did not evaluate other polymorphisms of the two genes. XRCC1 and hOGG1 contribute partially to DNA repair capacity in their respective pathways, and the polymorphisms of other genes that were not evaluated in this study could play a role in detecting COPD risk. We consider that large epidemiologic studies are also needed to explore other SNPs and DNA repair genes.
In conclusion, hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms are associated with the susceptibility of COPD. The risk of COPD is significantly elevated among current/light smokers with hOGG1 326Cys and XRCC1 399Gln.
1. Fletcher CM. Letter: Natural history of chronic bronchitis. BMJ 1976; 1: 1592-1593.
2. Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax 2006; 61: 935-939.
3. Sandford AJ, Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD: the genotype-environment interaction. Thorax 2002; 57: 736-741.
4. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004; 83: 1-1438.
5. Krokan HE, Nilsen H, Skorpen F, Otterlei M, Slupphaug G. Base excision repair of DNA in mammalian cells. FEBS Lett 2000; 476: 73-77.
6. Coleman CN, Harris JR. Current scientific issues related to clinical radiation oncology. Radiât Res 1998; 150: 125-133.
7. Vayssier-Taussat M, Camilli T, Aron Y, Meplan C, Hainaut P, Polla BS, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol 2001; 280: H1293-H1300.
8. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 2001; 61: 1354-1357.
9. Wei Q, Cheng L, Hong WK, Spitz MR. Reduced DNA repair capacity in lung cancer patients. Cancer Res 1996; 56: 4103-4107.
10. Shen H, Spitz MR, Qiao Y, Guo Z, Wang LE, Bosken CH, et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer 2003; 107: 84-88.
11. Friedberg EC. DNA damage and repair. Nature 2003; 421: 436-440.
12. Mohrenweiser HW, Wilson DM, Jones IM. Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes. Mutat Res 2003; 526: 93-125.
13. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 1997; 387: 147-163.
14. Kohno T, Shinmura K, Tosaka M, Tani M, Kim SR, Sugimura H, et al. Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene 1998; 16: 3219-3225.
15. Thompson LH, West MG. XRCC1 keeps DNA from getting stranded. Mutat Res 2000; 459: 1-18.
16. Abdel-Rahman SZ, El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett 2000; 159: 63-71.
17. David-Beabes GL, London SJ. Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians. Lung Cancer 2001; 34: 333-339.
18. Le Marchand L, Donlon T, Lum-Jones A, Seifried A, Wilkens LR. Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk. Cancer Epidemiol Biomarkers Prev 2002; 11: 409-412.
19. Park J, Chen L, Tockman MS, Elahi A, Lazarus P. The human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) DNA repair enzyme and its association with lung cancer risk. Pharmacogenetics 2004; 14; 103-109.
20. Park JY, Lee SY, Jeon HS, Bae NC, Chae SC, Joo S, et al. Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 23-27.
21. Sugimura H, Kohno T, Wakai K, Nagura K, Genka K, Igarashi H, et al. hOGG1 Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1999; 8: 669-674.
22. Zhou W, Liu G, Miller DP, Thurston SW, Xu LL, Wain JC, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2003; 12: 359-365.
23. Barbera JA, Peces-Barba G, Agusti AG, Izquierdo JL, Monso E, Montemayor T, et al. Clinical guidelines for the diagnosis and treatment of chronic obstructive pulmonary disease. Arch Bronconeumol 2001; 37: 297-316.
24. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163: 1256-1276.
25. Shen M, Hung RJ, Brennan P, Malaveille C, Donato F, Placidi D. et al. Polymorphisms of the DNA repair genes XRCC1, XRCC3, XPD, interaction with environmental exposures, and bladder cancer risk in a case-control study in northern Italy. Cancer Epidemiol Biomarkers Prev 2003; 12 (11 Pt 1): 1234-1240.
26. Sandford AJ, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med 2000; 21: 633-643.
27. Janssen K, Schlink K, Gotte W, Hippler B, Kaina B, Oesch F. DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326. Mutat Res 2001; 486: 207-216.
28. Dherin C, Radicella JP, Dizdaroglu M, Boiteux S. Excision of oxidatively damaged DNA bases by the human alpha-hOgg1 protein and the polymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found in human populations. Nucleic Acids Res 1999; 27: 4001-4007.
29. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst) 2003; 2: 955-969.
30. Caldecott KW. Mammalian DNA single-strand break repair: an X-ra(y)ted affair. Bioessays 2001; 23: 447-455.
31. Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD. et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 2001; 104: 107-117.
32. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res 1999; 59: 2557-2561.
33. Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer 2001; 92: 562-567.
34. Duell EJ, Wiencke JK, Cheng TJ, Varkonyi A, Zuo ZF, Ashok TD, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 2000; 21: 965-971.
35. Takezaki T, Gao CM, Wu JZ, Li ZY, Wang JD, Ding JH, et al. hOGG1 Ser (326) Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese. Int J Cancer 2002; 99: 624-627.
36. Wikman H, Risch A, Klimek F, Schmezer P, Spiegelhalder B, Dienemann H, et al. hOGG1 polymorphism and loss of heterozygosity (LOH): significance for lung cancer susceptibility in a Caucasian population. Int J Cancer 2000; 88: 932-937.
37. Elahi A, Zheng Z, Park J, Eyring K, McCaffrey T, Lazarus P. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. Carcinogenesis 2002; 23: 1229-1234.
38. Chen S, Tang D, Xue K, Xu L, Ma G, Hsu Y, et al. DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population. Carcinogenesis 2002; 23: 1321-1325.
39. Shen H, Xu Y, Qian Y, Yu R, Qin Y, Zhou L, et al. Polymorphisms of the DNA repair gene XRCC1 and risk of gastric cancer in a Chinese population. Int J Cancer 2000; 88: 601-606.
40. Dhenaut A, Boiteux S, Radicella JP. Characterization of the hOGG1 promoter and its expression during the cell cycle. Mutat Res 2000; 461: 109-118.
41. Paz-Elizur T, Krupsky M, Blumenstein S, Elinger D, Schechtman E, Livneh Z. DNA repair activity for oxidative damage and risk of lung cancer. J Natl Cancer Inst 2003; 95: 1312-1319.
42. Hu JJ, Smith TR, Miller MS, Mohrenweiser HW, Golden A, Case LD. Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis 2001; 22: 917-922.
43. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis 2001; 22:1437-1445.
44. Takanami T, Nakamura J, Kubota Y, Horiuchi S. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat Res 2005; 582: 135-145.
45. Wang Y, Spitz MR, Zhu Y, Dong Q, Shete S, Wu X. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst) 2003; 2: 901-908.
46. Ishida T, Takashima R, Fukayama M, Hamada C, Hippo Y, Fujii T, et al. New DNA polymorphisms of human MMH/OGG1 gene: prevalence of one polymorphism among lung-adenocarcinoma patients in Japanese. Int J Cancer 1999; 80: 18-21.
47. Marsin S, Vidal AE, Sossou M, Menissier-de Murcia J, Le Page F, Boiteux S, et al. Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1. J Biol Chem 2003; 278: 44068-44074.