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Mutagenesis Advance Access published online on September 2, 2008
Mutagenesis, doi:10.1093/mutage/gen046
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© The Author 2008. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

A meta-analysis on XRCC1 R399Q and R194W polymorphisms, smoking and bladder cancer risk

Tingjia Lao, Weiguo Gu and Qingshan Huang*

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, Peoples Republic of China

To elucidate the role of X-ray repair cross-complementing group 1 (XRCC1) R399Q and R194W genotypes in bladder cancer risk, all available studies were considered in the present meta-analysis, with 4152 patients and 5372 controls for R399Q and 3215 patients and 4313 controls for R194W. Studies were identified in PubMed up to June 2008. Overall, the 399Q allele showed no significant effect on bladder cancer compared to 399R allele in all subjects. Insignificant association between R399Q and bladder cancer was observed under other genetic contrasts in worldwide population, Caucasians and never-smokers. Among ever-smokers, protective effects of 399QQ genotype were observed under recessive model [P = 0.004, fixed-effects (FEs) model odds ratio (OR) = 0.65; 95% confidence interval (CI) (0.49, 0.86), I2 = 0% Pheterogeneity = 0.57] and homozygote contrast (P = 0.01, FE OR = 0.66; 95% CI (0.49, 0.90), I2 = 0%, Pheterogeneity = 0.76). No apparent effect of 194W allele compared to 194R on bladder cancer risk was found in all subjects and Caucasians. It indicated that XRCC1 R399Q and R194W might not be risk factors to bladder cancer, but the 399QQ genotype decreased susceptibility of bladder cancer under recessive model and homozygote contrast among ever-smokers. Further studies based on larger, stratified population were required to explore the role of XRCC1 polymorphisms in bladder cancer risk.


   Introduction
Top
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Bladder cancer rates the fourth most common malignancy among males in the Western world while eighth in females (1Go). Until now, the well-established risk factors for bladder cancer have been documented to cause direct and indirect DNA damage (2Go,3Go). Unrepaired DNA damage caused by chemical and physical agents in the environment such as smoking-related carcinogens may result in mutations and ultimately cancers (4Go). However, various types of DNA damage are repaired through multiple pathways, among which base excision repair (BER) repairs base damage and DNA single-strand breaks in human cells. This pathway is a multi-step process which involves several proteins (5Go), and the genes encoding for these proteins have been proposed as potential cancer susceptibility genes. The X-ray repair cross-complementing group 1 (XRCC1) protein constitutes one of the components in the BER pathway (6Go), which is found to have no catalytic activity but act physically as a scaffold by associating with DNA ligase III, DNA polymerase B, human AP (apurinic/apyrimidinic) endonuclease, polynucleotide kinase, as well as poly[adenosine diphosphate (ADP) ribose]polymerase (7Go,8Go). In addition, it serves as a single-strand break sensor (9Go). Mutant in XRCC1 is known to be associated with severe chromosome aberrations and deletions (10Go).

R399Q (exon 10, base 28152 G to A, arginine to glutamine) and R194W (exon 6, base 26304 C to T, arginine to tryptophane) are two common polymorphisms of XRCC1. The XRCC1 R399Q variant is located at the COOH-terminal side of the poly (ADP ribose) polymerase-interacting domain within a relatively non-conserved region between conserved residues of the BRCT (first described at the carboxyl terminus of the breast cancer protein BReast CAncer 1) domain, which is indicated as a protein–protein interaction module in many proteins involved in DNA repair (7Go). In addition, the variant may be related with several phenotypic alterations, including higher levels of sister chromatid exchange (11Go), aflatoxin B1–DNA adducts, glycophorin A mutations (12Go) and polyphenol DNA adducts (13Go). The R194W polymorphism, which occurs in nuclear antigen-binding region of the proliferating cell, is suggested to enhance individual DNA repair capability (14Go). So far, many studies have focussed on the associations between bladder cancer risk and DNA repair pathway gene polymorphisms. It has been reported that XRCC1 R399Q was associated with various cancer risks (15Go). Hung et al. (52Go) found that XRCC1 399QQ genotype was associated with increased risk of tobacco-related cancers among light smokers but decreased risk among heavy smokers, whereas for bladder cancer risk, inconsistent results were obtained (16Go–18Go). Studies on the polymorphism of XRCC1 R194W had also shown different trends of risk in bladder cancer, and none of the results were conclusive (12Go,19Go,20Go,52Go), owing perhaps to the relatively small sample size and different patient populations. Therefore, it is highly necessary to perform a quantitative and systematic study with rigorous methods. In the present study, a meta-analysis was performed from all eligible studies to address the association between XRCC1 polymorphisms (R399Q and R194W) and bladder cancer risk.


   Materials and methods
Top
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Identification and eligibility of relevant studies
Relevant studies were identified by searching the PubMed database up to June 2008 using the following keywords and subject terms: ‘bladder cancer', ‘X-ray repair cross-complementing group 1', ‘XRCC1’ and ‘polymorphism'. References cited in retrieved articles were screened to identify additional articles missed by the PubMed search. Eligible studies included in the meta-analysis had to meet all the following criteria: (i) distribution of R399Q and R194W genotypes in bladder cancer patients and in the controls should be determined, (ii) the studied population should be composed of unrelated individuals and pedigree data should be excluded, (iii) validated genotyping methods should be used, (iv) genotype distribution of the controls must be in Hardy–Weinberg equilibrium (HWE) and (v) the most recent and/or the largest study with extractable data should be included concerning studies with overlapping patients and the controls.

Data extraction
Two authors of the present study had collected the data independently and reached a consensus on all classified items. Genotypes of XRCC1 R399Q and R194W were collected on both patients and controls. First author, year of publication, ethnicity, country of study population and characteristics (smoking status, gender, age, sample size, type of sample for genotyping and other variables that can be sources of bias) of the patients and the controls were extracted.

Statistical analysis
The meta-analysis examined overall association between the XRCC1 R399Q allele Q and bladder cancer risk compared to allele R, as well as using homozygote contrast (QQ versus RR), the recessive genetic model [QQ versus (QR + RR)], the dominant genetic model [(QQ +QR) versus RR], QQ versus QR contrast and QR versus RR contrast. The same contrasts were performed for the XRCC1 R194W polymorphism.

Odds ratios (ORs) corresponding to 95% confidence interval (CI) were applied to assess the strength of association, and the OR was calculated according to the method of Woolf (21Go). A chi-square-based Q-statistic test (22Go) and an I2-test (23Go) were performed to assess the between-study heterogeneity. Heterogeneity was considered significant if the P-value of Q-statistic test is <0.10. A fixed-effects (FEs) model using the Mantel–Haenszel method and a random-effects (REs) model using the DerSimonian and Laird method were used to pool the results. With the absence of between-study heterogeneity, the two methods provide identical results. FEs are more appropriate when heterogeneity is not present. Both FEs model and REs model were used in Review Manager 4.2 software (24Go) and pooled ORs under both models were presented to facilitate the comparison. The significance of the pooled OR was determined by the Z-test; a P-value of <0.05 was considered significant. The influence of individual study on the summary OR was also evaluated by plotting the summary OR in the absence of each study in turn. For each genetic contrast, subgroup analysis according to ethnicity (Caucasian population) was considered for XRCC1 R399Q and R194W polymorphisms, while subgroup analysis according to smoking status (ever-smoker and never-smoker) was considered only for XRCC1 R399Q polymorphism because there were no sufficient data for R194W polymorphism (with only one study providing data on ever-smokers and two on never-smokers). Inverted funnel plots and the Egger's test were used to provide diagnosis of publication bias (25Go). An asymmetric plot suggested possible publication bias. The funnel plot asymmetry was assessed by Egger's linear regression test. The t-test was performed to determine the significance of the asymmetry, and a P-value of <0.05 was considered a significant publication bias.

HWE was tested by the chi-square test for goodness of fit using a web-based program (http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). Analyses were performed using the software Stata version 8.0, Review Manager 4.2. All P-values were two sided.


   Results
Top
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Eligibility
Articles on single-nucleotide polymorphisms (SNPs) exclusively of XRCC1 R399Q or R194W were selected in the present investigation. With our search criteria, a total of 23 papers were identified, 16 of which (16Go–18Go,26Go–38Go) investigated the association between bladder cancer risk and XRCC1 R399Q or R194W polymorphism. The study of Matullo et al. (30Go) and Kelsey et al. (18Go) were replaced by more updated reports (24Go,29Go); genotype distributions of the control population by Andrew et al. (37Go) were significantly deviated from HWE; no detailed genotyping information was included in Huang et al. (29Go). Therefore, these four were excluded. A total of 12 eligible articles described R399Q, 7 of them also providing data on R194W (Table I). Among these 12 eligible articles, 91.7% (11/12) stated that the age and sex status of the patient populations matched with that of controls. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) was used to validate genotype in seven articles, Taqman SNP genotyping assay was used in four articles and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used in one article (27Go). Blood samples were used in 10 articles for genotyping, buccal cell samples were used in Broberg et al. (27Go), and both blood samples and buccal cell samples were used in Figueroa et al. (28Go).


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  		Table I. Characteristics of eligible studies considered in the meta-analysis

 
In the 12 eligible articles, Stern et al. (32Go) provided data on two ethnicities––Africans and Caucasians. Each sub-population was treated as a separate study in our meta-analysis. Two articles provided data on mixed ethnicities (26Go,32Go), one on Asians, and the remaining eight articles reported on Caucasians. Finally, 13 studies were considered for R399Q polymorphism and 8 for R194W.

Meta-analysis database
A total of 4152 bladder cancer patients and 5372 controls were investigated for R399Q, while 3215 bladder cancer patients and 4313 controls for R194W. Details of the patients and controls were listed in Table I. Three studies were from North America, seven from Europe and two from Asia. Genotypes and allele frequencies of patients and controls for R399Q were shown in Table II, the allele frequencies calculated from the corresponding genotype distributions. Ever-smoker and never-smoker-based data for R399Q were shown in Tables III and IV, respectively. Genotypes and allele frequencies of patients and controls for R194W were listed in Table V. The 399R allele was less common among the Caucasian controls (65.6%) than the African (84.6%). The frequencies of 399R of ever-smoker and never-smoker population controls were 64.7% and 66.1%, respectively. Overall, the prevalence of RR homozygote was 43.2% and 69.2% in controls of Caucasian and African, respectively. The respective prevalence rates in these two populations of QR heterozygote were 44.7% and 30.7%, and the respective rates for QQ homozygote were 12.1% and 0%. Among the control of ever-smoker and never-smoker populations, the respective prevalence rates were 43.4% and 44.3% for RR homozygote, 42.5% and 43.7% for QR heterozygote and 14.1% and 12.1% for QQ homozygote. The 194R allele was slightly more common in controls of Caucasian (93.5%) than in those of African (88.5%). Overall, in control subjects of Caucasian and African, the prevalence was 88.2% and 94.7% for RR194 homozygote, 11.4% and 5.3% for R194W heterozygote and 0.4% and 0% for 194WW homozygote. Since there was only one study on the African population and one on the Asian population, subgroup analysis according to ethnicity was only considered for Caucasian population.


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  		Table II. Distribution of XRCC1 R399Q genotype and allele among patients and controls included in the meta-analysis

 


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  		Table III. Distribution of XRCC1 R399Q genotype and allele among ever-smokers included in the meta-analysis

 


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  		Table IV. Distribution of XRCC1 R399Q genotype and allele among never-smokers included in the meta-analysis

 


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  		Table V. Distribution of XRCC1 R194W genotype and allele among patients and controls included in the meta-analysis

 
Effect for allele and subgroup analysis
R399Q. No significant heterogeneity existed between the 13 comparisons (I2 = 0%, Pheterogeneity = 0.58) when considering R399Q allelic contrast (Q versus R). An FE model was used to pool the results (Figure 1A). There was no evidence that the Q allele was associated with bladder cancer risk among worldwide populations. The pooled OR was 1.00, 95% CI (0.94, 1.06) by the FEs model (P = 0.97) (Table VI). In order to study the ethnic effect, the subgroup meta-analysis was performed in the Caucasian population. No effect of 399Q on susceptibility was observed in subgroup of Caucasians [Figure 1B, P = 0.75, FE OR = 1.01, 95% CI (0.94, 1.09), I2 = 4.1%, Pheterogeneity = 0.40]. Meta-analysis under other contrasts (homozygote contrast, recessive and dominant genetic models, QQ versus QR contrast and QR versus RR contrast) suggested that the 399Q variant showed no association with bladder cancer risk in global subjects and Caucasians.


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  		Table VI. Summary of ORs for various genetic contrasts performed when investigating the association of R399Q and R194W polymorphisms with bladder cancer.

 


Figure 1
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  		Fig. 1. Meta-analysis of XRCC1 R399Q polymorphism in bladder cancer. The study is shown by a point estimate of the OR and the accompanying 95% CI. n Indicates the total number of Q allele, N indicates the total number of Q plus R alleles. Stern MC-B indicates the sub-population of African, Stern MC-W indicates the sub-population of Caucasians, Matullo G-A indicates Matullo et al. (31Go) and Matullo G-B indicates Matullo et al. (36Go). (A) Overall analysis in worldwide population under an FEs model. (B) Subgroup analysis in Caucasian population under an FEs model. (C) Subgroup analysis in ever-smokers under an FEs model. (D) Subgroup analysis in never-smokers under an FEs model.

 
Five out of the 13 studies consisting of 950 ever-smoker patients and 958 ever-smoker controls and six studies consisting of 340 never-smoker patients and 1557 never-smoker controls were used to examine the association between 399Q and bladder cancer risk. Among these articles, one (26Go) was replaced by the previous research (18Go), which provided detailed genotyping information of ever- and never-smokers. Although no evidence of association had been found between 399Q allele and bladder cancer risk in ever-smokers [Figure 1C, P = 0.06, FE OR = 0.88, 95% CI (0.77, 1.01), I2 = 0%, Pheterogeneity = 0.81] and never-smokers [Figure 1D, P = 0.51, FE OR = 1.06, 95% CI (0.88, 1.27), I2 = 0%, Pheterogeneity = 0.53], the recessive genetic model had suggested that the 399QQ genotype in ever-smoker population was more likely to reduce bladder cancer susceptibility [Figure 3A, P = 0.004, FE OR = 0.65; 95% CI (0.49, 0.86), I2 = 0%, Pheterogeneity = 0.57]. The homozygote contrast had also supported this conclusion in ever-smokers [Figure 3B, P = 0.01, FE OR = 0.66; 95% CI (0.49, 0.90), I2 = 0%, Pheterogeneity = 0.76]. No significant association for never-smoker population was found in various comparisons.

R194W. No significant heterogeneity was found in eight studies with respect to R194W allelic contrast in bladder cancer (Table VI). The FE model was used to pool the results (Figure 2A). There was no evidence that the 194W allele be associated with bladder cancer risk in all subjects [Figure 2A, P = 0.29, FE OR = 0.93, 95% CI (0.81, 1.06), I2 = 0%, Pheterogeneity = 0.45] and Caucasians [Figure 2B, P = 0.37, FE OR = 0.93, 95% CI (0.79, 1.10), I2 = 20.6%, Pheterogeneity = 0.28] (Table VI). R194W showed no association with bladder cancer risk under different genetic models in worldwide subjects and Caucasians.


Figure 2
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  		Fig. 2. Meta-analysis of XRCC1 R194W polymorphism in bladder cancer. The study is shown by a point estimate of the OR and the accompanying 95% CI. n Indicates the total number of W allele and N indicates the total number of W plus R alleles. Stern MC-B indicated the sub-population of African, Stern MC-W indicated the sub-population of Caucasians, Matullo G-A indicated Matullo et al. (31Go) and Matullo G-B indicated Matullo et al. (36Go). (A) Overall analysis in worldwide population under an FEs model. (B) Subgroup analysis in Caucasian population under an FEs model.

 
Sensitivity analysis
Sensitivity analysis was performed by sequential omission of individual studies under various comparisons in worldwide subjects and subgroups, respectively. When we investigated R399Q, the significance of pooled ORs was not influenced excessively by any single study (data not shown) on worldwide population, Caucasians or never-smoker population subgroups. However, in the ever-smoker subgroup analysis, when one study (18Go) was excluded, the pooled results turned out to be insignificant in recessive model [QQ versus (QR + RR)], whereas exclusion of any other studies did not influence the results. Furthermore, when any single study, except one (35Go), was excluded the pooled results were not significant in homozygote contrast (QQ versus RR). With only five studies included in the analysis, these results must be used with caution. More studies on subjects of smoking status should be recruited.

As to R194W, similar procedures on sensitivity analysis were performed. And none of the pooled results were significantly affected by any single study (data not shown).

Publication bias
Funnel plots and Egger's test were performed to assess publication bias (Figure 4). The data suggested that there was no evidence of publication bias in comparison of 399Q versus 399R (t = –0.23, P = 0.821), but for comparison between 194R allele and the 194W allele, significant publication bias was observed (t = –3.11, P = 0.021).


Figure 3
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  		Fig. 3. Meta-analysis of XRCC1 R399Q polymorphism in bladder cancer among ever-smokers. The study is shown by a point estimate of the OR and the accompanying 95% CI. (A) Recessive model contrast under an FEs model. n Indicates the total number of QQ genotypes and N indicates the total number of QR plus QQ and RR genotypes. (B) Homozygote contrast under an FEs model. n Indicates the total number of QQ genotypes and N indicates the total number of QQ plus RR genotypes.

 


Figure 4
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  		Fig. 4. Begg's funnel plot of the Egger's test of allele comparison for publication bias. (A) Funnel plot for Q versus R allele comparison in R399Q polymorphism; (B) Funnel plot for W versus R allele in R194W polymorphism.

 

   Discussion
Top
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
In the present study, a meta-analysis was performed to examine the association between XRCC1 polymorphisms and bladder cancer risk, by critically reviewing 13 studies on XRCC1 R399Q genotype (a total of 4152 bladder cancer patients and 5372 controls) and 8 studies on XRCC1 R194W genotype (3215 bladder cancer patients and 4313 controls). The results were consistent with a previous meta-analysis (28Go), which was based on seven studies from 2001 to 2006. However, our study was more stringent and comprehensive. Firstly, more up to date studies were recruited to provide statistically significant results. Secondly, the association between XRCC1 R194W and bladder cancer risk had been explored in detail. And most importantly, stratified analyses have been performed for never- and ever-smokers to investigate the association between XRCC1 R399Q and bladder cancer risk.

No association between XRCC1 R399Q polymorphism and bladder cancer risk was found in either worldwide population or Caucasians for allelic contrast and other genetic contrasts. However, among ever-smokers, the QQ genotype tended to reduce the risk of bladder cancer compared to other genotypes (QQ versus QR + RR or QQ versus RR). For R194W polymorphism, it was shown to have significant effect on susceptibility to bladder cancer in neither worldwide population nor Caucasians.

DNA repair is well known as a ‘double-edged sword’ in carcinogenesis studies. Epidemiological evidence supports that DNA repair capacity is one of the determinants of genetic susceptibility to cancer (39Go–41Go). On the other hand, tumours with enhanced DNA repair capacity would exhibit an intrinsic resistance to the anti-tumour activity during chemotherapy and radiotherapy (42Go). Fluorouracil (5-FU)/oxaliplatin-based chemotherapy induces DNA damages and causes cell death (43Go). These damages are mainly repaired by the BER pathway. A 5-fold greater incidence of failure by 5-FU/oxaliplatin therapy had been reported for metastatic colorectal cancer patients with XRCC1 R399Q (QQ or QR) substitution compared with that of the RR genotype, suggesting that the polymorphism was associated with resistance to oxaliplatin/5-FU therapy (44Go). In addition, it had been found that XRCC1 codon 194 variant was having a significant protective effect on development of late radiotherapy reactions in normal tissue (45Go). Furthermore, Sak et al. (46Go) indicated that high levels of XRCC1 protein expression were associated with improved cancer-specific survival in patients following radical radiotherapy. Therefore, although XRCC1 R399Q and R194W polymorphisms had not yet been defined tight association with the incidence of bladder cancer, they might play some important roles in the drug sensitivity during chemotherapy and radio sensitivity during radiotherapy.

Smoking is the dominant risk factor for several epithelial cancers (47Go). It constitutes the most important cause in the incidence of bladder cancer, with cigarette smokers 2- to 4-fold higher than never-smokers (48Go,49Go). Tobacco smoke contains chemicals such as 4-(methylnitrosamino)-1-(3-pyridyl), 1-butanone, catechol and hydroquinone that generate free radicals and induce oxidative damage to DNA (50Go,51Go). Therefore, constitutional variation in the ability to repair DNA base damage might lead to smoking-related cancers. This meta-analysis indicated that XRCC1 399QQ genotype was associated with decreased bladder cancer risk among ever-smokers under the recessive genetic model and the homozygote contrast. The results were in accordance with previous study (33Go) and others involving tobacco-related cancers among heavy smokers (52Go). However, contradictory results were also been noted (18Go,30Go,34Go,53Go).

Previous studies showed that the 399Q allele may be associated with higher mutagen sensitivity, higher levels of carcinogen adducts, mutations as well as sister chromatid exchanges (13Go) and, inducing theoretically, higher incidence of cancer. On the contrary, reduced risk among ever-smokers carrying the 399QQ genotype was observed in this study, and the mechanistic basis required further examination. As reported by Matullo et al. (54Go), among never-smokers, XRCC1 399QQ carriers exhibited higher DNA adduct levels than RR carriers, whereas among current smokers, lower but insignificant DNA adduct levels were detected. It was probable that increased levels of DNA damage resulted from tobacco smoking lead to enhanced apoptosis at the time of cell division and yield a reduced risk of bladder cancer. Alternatively, enhanced DNA repair capacity would be induced by tobacco smoking. Wang et al. (19Go) found lower levels of chromosome breaks in healthy heavy smokers (>42 pack-years) than in never-smokers. Moreover, lower level of 8-oxoguanine in lymphocytes among ever-smokers as compared to never-smokers had also been reported (55Go,56Go). However, the explicit effect of smoking and XRCC1 R399Q or R194W polymorphism on bladder cancer risk needs further investigation.

Apparently, there are some limitations inherent in meta-analysis per se. Public bias of XRCC1 R194W polymorphism was considered as a possible limitation in our study. The formal evaluation indicated that the publication bias existed in those studies, reporting 194W genotype with a decreased bladder cancer risk. If such bias did exist, it would reduce the creditability of the meta-analysis (Figure 4B). Selection bias in recruiting control subjects could represent another potential bias, especially when the genotype distribution of R399Q polymorphism among control subjects were slightly departed from HWE in one study (26Go), although its exclusion from the analysis did not affect significantly the summary ORs. On account of different populations used in our analysis, population stratification bias may also occur. Nevertheless, such bias could be minimized using population-based studies with well-matched case–control for ethnicity (57Go).

The variability among populations, together with the probability of false negatives due to underpowered studies and of false positives due to multiple analyses, might lead to conflicting conclusions across different studies. In our meta-analysis, a relatively large number of studies were included, and the false-negative and false-positive findings would neutralize each other.

By reviewing studies on other cancers, we found that the distribution of allele frequencies in the Asian controls were similar to that in Caucasians (data not shown). Theoretically, this indicated similar effect of XRCC1 R399Q and R194W polymorphisms on cancer risks among Asians. However, the valid conclusion cannot be drawn only by studying genotype distribution of the existing healthy controls. Other factors like diet and genetic background must be taken into full account. As a result, more in-depth research on these polymorphisms and bladder cancer risk will be of choice for the Asians.

The cigarette smoke is a complex mixture of substances. Since XRCC1 contributes only partially to BER, it is possible that polymorphism of other genes may play a more important role to bladder cancer risk. Therefore, more SNPs of a specific gene should be further considered and, especially, the combined functions of different SNPs in the XRCC1 gene. Furthermore, the participants with obtained smoking status in current meta-analysis were simply divided into never- and ever-groups, and then, quantitative data of smoking were not available for analyses. Complications caused by the cumulative cigarette consumption (heavy and light smoking) are expected. It had been reported that the XRCC1 399QQ genotype was associated with increased risk of tobacco-related cancers among light smokers but decreased risk among heavy smokers (52Go). Quantitative studies on gene–environment interaction between tobacco smoking and the polymorphisms of XRCC1, with more patients and quantitative data of smoking status are badly needed.

In conclusion, our meta-analysis had suggested that the XRCC1 R399Q and R194W polymorphisms had no association with bladder cancer risk in all examined patients, whereas there was an association between XRCC1 399QQ genotype and decreased bladder cancer risk under homozygote contrast and recessive model among ever-smokers. Larger samples among different populations, especially studies with respect to smoking–gene interactions, were needed to clarify possible roles of R399Q and R194W in bladder cancer.


   Funding
Top
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
The Special Foundation for bio-medicine of Shanghai Hi-Tech United Bio-Technological R&D Co. Ltd.


   Acknowledgments
 
We are grateful for Professors Deming Su, Zuyu Luo, Yang Zhong and Gui-Shuang Ying for their generous advice.


   Notes
 
* To whom correspondence should be addressed. Tel: +86 21 6564 2814; Fax: +86 21 5899 4819; Email: qshuang{at}fudan.edu.cn


   References
Top
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received on April 14, 2008; revised on July 10, 2008; accepted on July 11, 2008.


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