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Original article

hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms associated with chronic obstructive pulmonary disease

YANG, Shi-fang; XU, Yong-jian; XIE, Jun-gang; ZHANG, Zhen-xiang

Editor(s): QIAN, Shou-chu; WANG, Mou-yue

Author Information
doi: 10.3760/cma.j.issn.0366-6999.2009.08.016
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Abstract

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.

METHODS

Study subjects

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.

Laboratory methods

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.

Figure. A.
Figure. A.:
Analysis of the hOGG1 Ser326Cys polymorphism. 1: Ser/Ser genotype; 2: Cys/Cys genotype; 3: Ser/Cys genotype. B. Analysis of the XRCC1 Arg399Gln polymorphism. 1: Arg/Arg genotype; 2: Gln/Gln genotype; 3: Arg/Gln genotype.

Statistical analysis

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.

RESULTS

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).

Table 1
Table 1:
Characteristics of cases and controls

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).

Table 2
Table 2:
hOGG1 codon 326 genotype and XRCC1 codon 399 genotype frequencies and odds radios in COPD patients and controls

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.

Table 3
Table 3:
Association between the polymorphisms of hOGG1 Ser326Cys and XRCC1 Arg399Gln, and combined these genotypes and COPD according to smoking status
Table 4
Table 4:
Association between the polymorphisms of hOGG1 Ser326Cys and XRCC1 Arg399Gln, and combined these genotypes and COPD according to smoking exposure

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).

DISCUSSION

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.

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Keywords:

chronic obstructive pulmonary disease; cigarette smoke; DNA damage; 8-oxoG DNA glycosylase 1; X-ray repair cross-complementing group 1

© 2009 Chinese Medical Association