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1.
We have recently demonstrated a significant dose–response relationship between vinyl chloride exposure and mutant p53 biomarkers in humans. The aim of this study was to examine a common polymorphism in the DNA repair gene XRCC1 as a potential biomarker of susceptibility modifying this relationship, consistent with the known mechanism of production of p53 mutations via vinyl chloride-induced etheno-DNA adducts, which are repaired by XRCC1. A cohort of 211 French vinyl chloride workers were genotyped for the XRCC1 codon 399 polymorphism (CGG>CAG; Arg>Gln). Among the homozygous ArgArg individuals, 34% were biomarker positive compared with 47% in the heterozygous ArgGln individuals (adjusted odds ratio 1.73, 95% CI0.93–3.22) and 66% in the homozygous GlnGln individuals (adjusted odds ratio 3.95, 95% CI 1.68–9.28), with a significant trend for increasing Gln allele dosage (p=0.002). These preliminary results suggest that a common polymorphism in a DNA repair gene can be an important biomarker of susceptibility for chemically induced genetic damage.  相似文献   

2.
The authors have recently demonstrated a significant gene-environment interaction between vinyl chloride exposure and polymorphisms in the DNA repair protein XRCC1 on the occurrence of mutant p53 biomarkers of vinyl chloride-induced genetic damage. The aim of this study was to examine the polymorphisms in the glutathione S-transferases (GSTs) as potential modifiers of this relationship, since these enzymes may be involved in the phase II metabolism of the reactive intermediates of vinyl chloride. A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1. Although no independent, statistically significant effect of these polymorphisms on the occurrence of the mutant p53 biomarker was found, the null GSTM1 and null GSTT1 polymorphisms were found to interact with the XRCC 1 polymorphism to increase the occurrence of the biomarker such that, for example, workers with at least one variant XRCC1 allele who were null for both GSTM1 and GSTT1 had a significant odds ratio for the biomarker (OR =8.4, 95% CI = 1.3 54.0) compared with workers who were wild-type for all alleles, controlling for potential confounders including cumulative vinyl chloride exposure.  相似文献   

3.
Y. Li  M. Zhou  M.-J. Marion  S. Lee 《Biomarkers》2013,18(1):72-79
The authors have recently demonstrated a significant gene–environment interaction between vinyl chloride exposure and polymorphisms in the DNA repair protein XRCC1 on the occurrence of mutant p53 biomarkers of vinyl chloride-induced genetic damage. The aim of this study was to examine the polymorphisms in the glutathione S-transferases (GSTs) as potential modifiers of this relationship, since these enzymes may be involved in the phase II metabolism of the reactive intermediates of vinyl chloride. A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1. Although no independent, statistically significant effect of these polymorphisms on the occurrence of the mutant p53 biomarker was found, the null GSTM1 and null GSTT1 polymorphisms were found to interact with the XRCC1 polymorphism to increase the occurrence of the biomarker such that, for example, workers with at least one variant XRCC1 allele who were null for both GSTM1 and GSTT1 had a significant odds ratio for the biomarker (OR=8.4, 95% CI=1.3–54.0) compared with workers who were wild-type for all alleles, controlling for potential confounders including cumulative vinyl chloride exposure.  相似文献   

4.
It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the χ(2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.  相似文献   

5.
ABSTRACT: BACKGROUND: Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage. FINDINGS: The median (P25-P75) of Olive tail moment was 0.93 (0.58-1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46-1.35) for GA heterozygote and 0.50 (0.43-0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44-1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15-0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage. CONCLUSION: The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.  相似文献   

6.
Context: X-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair, homologous recombination repair, and nucleotide excision repair of DNA repair pathways, respectively. Previous studies have demonstrated that their gene polymorphisms were associated with some cancer susceptibility. Objective and design: To investigate the effect of XPD Lys751Gln, XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 Thr241Met polymorphisms on the risk of nasopharyngeal carcinoma (NPC), a population-based case-control study of 153 NPC patients and 168 healthy controls among Sichuan population was conducted. Results: Our results showed that XRCC1 codon 194 Trp allele was associated with an increased risk of NPC (odds ratio [OR] = 1.828, 95% confidence interval [CI]: 1.286-2.598), and XPD codon 751Gln allele was associated with a borderline decrease of NPC (OR = 0.600, 95% CI: 0.361-1.000); combination analysis showed that individuals with both putative genotypes of XPD codon 751 Lys/Lys and XRCC1 codon 194 Arg/Trp or Trp/Trp have a significantly elevated risk of NPC (OR = 2.708, 95% CI: 1.338-5.478). Conclusion: The results indicated that XRCC1 codon 194 Trp allele and XPD codon 751 Lys allele may be contributing factors in the risk of NPC.  相似文献   

7.
The aim of present study was to investigate the role of the X-ray repair cross-complementing protein1 (XRCC1) and Tumor protein p53 (Tp53) polymorphisms in Uterine Leiomyoma (UL) susceptibility in southeastern Iran. This case control study was performed on 139 women with UL and 149 age, BMI and ethnicity matched healthy women. All women were genotyped for the XRCC1 Arg399Gln, XRCC1 Arg194Trp and Tp53 Arg72Pro polymorphisms. The frequency of Tp53 72 Pro/Pro genotype was significantly higher in UL women compared to controls. The risk of UL was 1.5 fold higher in women with the Pro/Pro genotype (OR, 1.5 [95% CI, 1.1 to 2.1], p = 0.012). Moreover, the frequency of the Pro allele was significantly higher in the UL women. Although the frequency of XRCC1 Arg399Gln genotypes did not significantly differ between UL and control groups before adjusting for age, there was an association between the XRCC1 Arg/Gln genotype and UL after adjusting for age (OR, 1.8 [95% CI, 1.1 to 3]). No association was observed between the XRCC1 Arg194Trp polymorphism and UL. The Pro/Pro genotype of Tp53 Arg72Pro polymorphism was associated with UL susceptibility. In addition, the XRCC1 Arg/Gln genotype was associated with increased risk of UL after adjusting for age.  相似文献   

8.
Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.  相似文献   

9.
Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p=0.001) for the Asp/Glu genotype and 2.39 (p=0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR=0.32, p=0.024; OR=0.25, p=0.028; OR=0.51, p=0.033, respectively). No associations with lung cancer risk were found for the XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.  相似文献   

10.
The X-ray repair cross-complementing group 1 (XRCC1) gene, one of over 20 genes that participate in the base excision repair pathway, is thought to account for differences in susceptibility to hepatocellular carcinoma. To assess the relationship between the XRCC1 Arg399Gln polymorphism and the risk of hepatocellular carcinoma (HCC), we performed a meta-analysis. All the relevant studies were extracted from PubMed, Embase, the Chinese biomedicine databases, the Chinese national knowledge infrastructure, and the Wanfang databases (prior to August 2012). The meta-analysis was performed using all eligible studies, which covered a total of 2,554 cases and 3,320 controls, to examine the association between XRCC1 Arg399Gln polymorphism and the risk of HCC. Our analysis suggested that the variant genotypes of the XRCC1 Arg399Gln gene were associated with a significantly increased risk of HCC in a co-dominant model (Arg/Gln vs. Arg/Arg, odd ratios [OR] 1.39, 95 % confidence interval [CI] 1.08–1.79; Gln/Gln vs. Arg/Arg, OR 1.26, 95 % CI 1.04–1.52) and a dominant model (Arg/Gln + Gln/Gln vs. Arg/Arg OR 1.36, 95 % CI 1.07–1.72), whereas no association was observed in the recessive model (Gln/Gln vs. Arg/Gln + Arg/Arg, OR 1.05, 95 % CI 0.91–1.21). The results of the subgroup analysis by ethnicity indicated that the XRCC1 Arg399Gln polymorphism was associated with increased risk of HCC in Asian populations using the co-dominant model (Arg/Gln vs. Arg/Arg, OR 1.41, 95 % CI 1.06–1.87) and the dominant model (Gln/Gln vs. Arg/Gln + Arg/Arg, OR 1.35, 95 % CI 1.03–1.76). Our analysis provides evidence that the XRCC1 Arg399Gln polymorphism may be associated with a higher risk of HCC, especially among Asian populations.  相似文献   

11.
We have recently suggested that polymorphisms in metabolism and repair pathways may play a role in modulating the effects of exposure to the carcinogen vinyl chloride in the production of biomarkers of its mutagenic damage. The aim of the present study was to extend these observations by examining gene–environment interactions between several common polymorphisms in the DNA repair genes XRCC1 and ERCC2/XPD and vinyl chloride exposure on the production of vinyl chloride-induced biomarkers of mutation. A cohort of 546 French vinyl chloride workers were genotyped for the XRCC1 codon 194 (Arg>Trp; rs1799782), 280 (Arg>His; rs25489) and 399 (Arg>Gln; rs25487) polymorphisms and the ERCC2/XPD codon 312 (Asp>Asn; rs1799793) and 751 (Lys>Gln; rs13181) polymorphisms. The results demonstrated a statistically significant allele dosage effect of the XRCC1 399 variant on the production of the vinyl chloride-induced mutant p53 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p = 0.03), with a potentially supramultiplicative gene–environment interaction. In addition, the results demonstrate statistically significant allele dosage effects of the ERCC2/XPD 312 and 751 variants on the production of the vinyl chloride-induced mutant ras-p21 biomarker, even after controlling for confounders including cumulative vinyl chloride exposure (p < 0.0001 and p = 0.0006, respectively), with a potentially supramultiplicative gene–environment interaction for the codon 751 allele. Finally, the results suggest potential supramultiplicative gene–gene interactions between CYP2E1 (c2 allele; rs3813867) and ERCC2/XPD polymorphisms that are consistent with the proposed carcinogenic pathway for vinyl chloride, which requires metabolic activation by CYP2E1 to reactive intermediates that form DNA adducts that, if not removed by DNA repair mechanisms, result in oncogenic mutations.  相似文献   

12.
Association between the polymorphism of DNA repair genes XRCC1 Arg399ln and XRCC3 Thr241Met and the frequency of chromosomal aberrations in the uranium workers was studied. The Gln/Gln genotype of gene XRCC1 was associated with a significant increase in the number of chromosomal aberrations as compared to the corresponding homozygous wild type Arg/Arg (p < 0.05). The frequency of chromosomal aberrations in heterozygous carriers of the XRCC3gene Thr/Met was lower than in the homozygous carriers of the wild type Thr/Thr (p < 0.001).  相似文献   

13.
Endometriosis shows some characteristics of malignancy, including local invasion and aggressive spread to distant organs. The pathology of endometriosis may involve a complex interaction among genetic defects, DNA repairing defects and environmental factors. Since DNA repair capacity is closely related to the sustaining of the genomic stability, an XRCC1 Arg399Gln polymorphism was performed to evaluate the possible association with endometriosis in this paper. Recruited adult females were divided into two groups: endometriosis group (n = 141) and non-endometriosis group (n = 100). Genomic DNA was obtained from their peripheral leukocytes. DNA fragment coding XRCC1 Arg399Gln polymorphism was amplified by PCR and subsequently digested with MspI, and then the genotypes and allelic frequencies in both groups were compared. The genotype distribution and allelic frequency of XRCC1 Arg399Gln polymorphism was significantly different (P < 0.05). The partition of the "GG" homozygote in the patient group was greater than that in the control group, which means that for those people with more G allele, they will have higher risk for endometriosis. We concluded that XRCC1 Arg399Gln polymorphism is associated with higher susceptibility to endometriosis and XRCC1 Arg399Gln polymorphism might be a useful biomarker for endometriosis.  相似文献   

14.
XRCC genes (X-ray cross-complementing group) were discovered mainly for their roles in protecting mammalian cells against damage caused by ionizing radiation. Studies determined that these genes are important in the genetic stability of DNA. Although the loss of some of these genes does not necessarily confer high levels of sensitivity to radiation, they have been found to represent important components of various pathways of DNA repair. To ensure the integrity of the genome, a complex system of DNA repair was developed. Base excision repair is the first defense mechanism of cells against DNA damage and a major event in preventing mutagenesis. Repair genes may play an important role in maintaining genomic stability through different pathways that are mediated by base excision. In the present study, we examined XRCC1Arg194Trp and XRCC1Arg399Gln polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. Patients who had the allele Trp of the XRCC1Arg194Trp polymorphism had an increased risk of tumor development (OR = 8.80; confidence interval at 95% (95%CI) = 4.37-17.70; P < 0.001), as did the allele Gln of XRCC1Arg399Gln (OR = 1.01; 95%CI = 0.53-1.93; P = 0.971). Comparison of overall survival of patients did not show significant differences. We suggest that XRCC1Arg194Trp and XRCC1Arg399Gln polymorphisms are involved in susceptibility for developing astrocytomas and glioblastomas.  相似文献   

15.
DNA repair proteins maintain DNA integrity; polymorphisms in genes coding for these proteins can increase susceptibility to colorectal cancer (CRC) development. We analyzed a possible association of MLH1 -93G>A and 655A>G and XRCC1 Arg194Trp and Arg399Gln polymorphisms with CRC in Mexican patients. Genomic DNA samples were obtained from peripheral blood of 108 individuals with CRC (study group) at diagnosis and 120 blood donors (control group) from Western Mexico; both groups were mestizos. The polymorphisms were detected by PCR-RFLP. Association was estimated by calculating the odds ratio (OR). We found that the MLH1 and XRCC1 polymorphisms were in Hardy- Weinberg equilibrium. The MLH1 655A>G polymorphism in the 655G allele was associated with a 2-fold increase risk for CRC (OR = 2.04 and 95% confidence interval (95%CI) = 1.12-3.69; P < 0.01), while the MLH1 -93G>A polymorphism allele was associated with a protective effect (OR = 0.60, 95%CI = 0.40-0.89; P = 0.01 in the -93A allele and OR = 0.32, 95%CI = 0.13-0.79; P = 0.01 in the AA genotype). The XRCC1 Arg194Trp and Arg399Gln polymorphisms did not show any significant associations. In conclusion, we found that MLH1 -93G>A and 655A>G polymorphisms are associated with CRC in Mexican patients.  相似文献   

16.
Polymorphisms of DNA repair genes are associated with renal cell carcinoma   总被引:2,自引:0,他引:2  
DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity and may influence an individual's susceptibility to carcinogenesis. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been shown to cause a reduction in repair activity. We hypothesized that SNPs of DNA repair genes may be a risk factor for renal cell carcinoma (RCC). To test this hypothesis, DNA samples from 112 cases of renal cell cancer and healthy controls (n=180) were analyzed by PCR-RFLP to determine the genotypic frequency of six different polymorphic loci on five DNA repair genes (XRCC1, XPC, ERCC1, XRCC3, and XRCC7). The chi(2) test was applied to compare the genotype frequency between patients and controls. We found that the frequency of 399Gln variant at XRCC1 Arg399Gln was significantly higher in RCC cases than in controls (OR=2.83, 95%CI=1.24-6.49, P=0.01). The frequency of T-A haplotype of XRCC1 194 Trp and XRCC1 399Gln was significantly higher in RCC than controls. No differences in genotypes were observed at the other sites. This is the first report on SNPs of DNA repair genes in renal cell carcinoma that suggests XRCC1 399Gln polymorphism may be a risk factor for RCC. Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC.  相似文献   

17.
The objective was to study the relationship between the polymorphisms of the DNA repair gene XRCC1 Arg399Gln, Arg194Trp, and Arg280His uterine leiomyoma in a Chinese population. In the case–control study, we compared the XRCC1 gene polymorphism of 136 uterine leiomyoma patients and 140 healthy controls by using the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The results suggested that the genotype Arg/Arg of codon 280 was significantly different from its heterozygote (odds ratio [OR] = 3.633, 95% confidence interval [CI]: 2.147–6.148). In conclusion, the results suggest that polymorphism of XRCC1 Arg280His was associated with the increased risk of uterine leiomyoma in a Chinese population.  相似文献   

18.
The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung   总被引:30,自引:0,他引:30  
Defects in the repair and maintenance of DNA increase risk for cancer. X-ray cross-complementing group 1 protein (XRCC1) is involved with the repair of DNA single-strand breaks. A nucleotide substitution of guanine to adenine leading to a non-conservative amino acid change was identified in the XRCC1 gene at codon 399 (Arg/Gln). This change is associated with higher levels of aflatoxin B1-adducts and glycophorin A somatic mutations. A case-control study was conducted to test the hypothesis that the 399Gln allele is positively associated with risk for adenocarcinoma of the lung. XRCC1 genotypes were assessed at codon 399 in 172 cases of lung adenocarcinoma and 143 cancer-free controls. Two ethnic populations were represented, non-Hispanic White and Hispanic. The distribution of XRCC1 genotypes differed between cases and controls. Among cases, 47.7% were Arg/Arg, 35.5% were Arg/Gln, and 16.9% were Gln/Gln. Among controls, XRCC1 allele frequencies were 45.5% for Arg/Arg, 44.8% for Arg/Gln, and 9.8% for Gln/Gln. Logistic regression analysis was used to assess the association between lung adenocarcinoma and the G/G genotype relative to the A/A or A/G genotypes. In non-Hispanic White participants, the lung cancer risk associated with the G/G genotype increased significantly after adjustment for age (OR=2.81; 95% CI, 1.2-7.9; P=0.03) and increased further after adjustment for smoking (OR=3.25; 95% CI, 1.2-10.7; P=0.03). Among all groups, a significant association was found between the G/G homozygote and lung cancer (OR=2.45; 95% CI, 1.1-5.8; P=0.03) after adjustment for age, ethnicity, and smoking. This study links a functional polymorphism in the critical repair gene XRCC1 to risk for adenocarcinoma of the lung.  相似文献   

19.
Genetic polymorphisms are increasingly recognized as sources of variability not only in toxicokinetic but also in toxicodynamic response to environmental agents. XRCC1 is involved in base excision repair (BER) of DNA; it has variant genotypes that are associated with modified repair function. This analysis focuses on four polymorphisms: three in the coding region that affect protein structure and one in an upstream regulatory sequence that affects gene expression. The Arg399Gln variant is the most widely studied with evidence supporting a quantitative effect of genotype on phenotype. The homozygous variant (Gln/Gln) can have 3-4-fold diminished capacity to remove DNA adducts and oxidized DNA damage. This variant is relatively common in Caucasians and Asians where approximately 10% are homozygous variant. In contrast, the Arg194Trp variant appears to protect against genotoxic effects although the degree to which DNA repair is enhanced by this polymorphism is uncertain. The homozygous variant is rare in Caucasians and African Americans but it is present at 7% in Asians. A third coding region polymorphism at codon 280 appears to decrease repair function but additional quantitative information is needed and the homozygous variant is rare across populations studied. A polymorphism in an upstream promoter binding sequence (-77T>C) appears to lower XRCC1 levels by decreasing gene expression. Based upon genotype effect on phenotype and allele frequency, the current analysis finds that the codon 399 and upstream (-77) polymorphisms have the greatest potential to affect the toxicodynamic response to DNA damaging agents. However, the implications for risk assessment are limited by the likelihood that polymorphisms in multiple BER genes interact to modulate DNA repair.  相似文献   

20.
Background: Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non‐neoplastic gastric mucosa. Methods: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP‐kinase and CDH1) loci, assessed by Methylation‐Specific‐Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. Results: Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP‐kinase (adjusted OR = 0.30, 95%CI = 0.13–0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19–0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and <50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01–2.62, p = .045). Conclusion: XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP‐kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM‐related gastric carcinogenesis.  相似文献   

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