DNA修复基因XRCC1 Arg194Trp Arg280His和Arg399Gln多态性与前列腺癌相关性的Meta分析

目的探讨DNA修复基因X线修复交叉互补因子1（XRCC1）主要单核苷酸多态性与前列腺癌易感性的关系。方法在MEDLINE、EMBASE和OVID数据库上检索文献,收集及提取符合纳入标准的以XRCC1密码子194、280、399多态性与前列腺癌易感性为内容的病例对照研究文献,应用Stata统计软件进行Meta分析,比值比（ORs）及其95%可信区间（95%CI）评价关联强度;应用SPSS软件分析吸烟与前列腺癌关系,OR？评价其相对危险度。结果 XRCC1 399 Gln/Gln和XRCC1 280 Arg/His与前列腺癌的发病风险有关（Gln/Gln vs Arg/Arg：OR？=1.27,95%CI=1.02～1.59;Arg/His vs Arg/Arg：OR？=1.66,95%CI=1.09～2.52）,尤其在亚组分析中亚洲人的Gln/Gln明显增加了前列腺癌的发病风险（OR？=1.52,95%CI=1.18～1.96）;Arg194Trp与前列腺癌的发病风险无明显关联。吸烟是前列腺癌的危险因素（χ2=13.974,P=0.000,OR？=1.22）。结论 XRCC1 399 Gln/Gln和280 Arg/His可能与前列腺癌的易感性相关。     

Polymorphisms of XRCC1 gene and risk of gastric cardiac adenocarcinoma

X-ray repair cross complementing 1 (XRCC1) protein plays an important role in base excision repair. Single nucleotide polymorphisms (SNPs) in XRCC1 gene may affect DNA repairing ability and genetic susceptibility to cancer. This study was designed to investigate the correlation of XRCC1 Arg194Trp Arg280His and Arg399Gln SNPs with the risk of gastric cardiac adenocarcinoma (GCA). Genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism assay in 455 patients with GCA and 650 age- and sex-matched controls. We did not find any significant difference in allele and genotype distributions of Arg194Trp Arg399Gln between the groups ( P  > 0.05). However, a significant increase in GCA risk was seen among smokers if they carried at least one XRCC1 280His ( Arg280His  +  His280His ) genotype (odds ratio = 1.59, 95% confidence interval = 1.01–2.51) compared with smokers not carrying these genotype. Our results indicated that XRCC1 Arg194Trp and Arg 399 Gln SNPs might not be associated with the risk of GCA. However, smokers with His allele at codon 280 had a significantly increased risk of GCA.     

X-ray repair cross-complementing group 1 polymorphisms and hepatocellular carcinoma: a meta-analysis

AIM: To perform a systematic meta-analysis to investigate the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and hepatocellular carcinoma (HCC) risk.METHODS: Relevant studies extracted from PubMed, Embase, Wanfang, VIP and the Chinese National Knowledge Infrastructure databases up to March 2012 were included in the study. Stata software, version 11.0, was used for the statistical analysis. The odds ratios (ORs) and 95% confidence interval (CI) of the XRCC1 polymorphisms in HCC patients were analyzed and compared with healthy controls. The meta-analysis was performed using fixed-effect or random-effect methods, depending on the absence or presence of significant heterogeneity.RESULTS: Eleven studies with 2075 HCC cases and 2604 controls met our eligibility criteria (four studies, 888 cases and 938 controls for Arg194Trp, four studies, 858 cases and 880 controls for Arg280His, and nine studies, 1845 cases and 2401 controls for Arg399Gln). The meta-analysis revealed no associations between the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene and HCC risk under all contrast models (codominant, dominant and recessive models) in the overall analysis and sensitivity analysis (the studies with controls not in the Hardy-Weinberg equilibrium were excluded). For XRCC1 Arg280His polymorphism, the overall analysis revealed the significant association between the His/His genotype and the increased risk of HCC (His/His vs Arg/Arg model, OR: 1.96, 95% CI: 1.03-3.75, P = 0.04). However, sensitivity analysis showed an altered pattern of result and non-significant association (OR: 2.06, 95% CI: 0.67-6.25, P = 0.20). The heterogeneity hypothesis test did not reveal any heterogeneity, and Begg’s and Egger’s tests did not find any obvious publication bias.CONCLUSION: The XRCC1 Arg194Trp and Arg399Gln polymorphisms are not associated with HCC risk. More rigorous association studies are needed to verify the involvement of XRCC1 Arg280His polymorphism in HCC susceptibility.     

XRCC1 genetic polymorphism Arg399Gln and hepatocellular carcinoma risk: a meta‐analysis

Background: Studies investigating the association between X‐ray repair cross‐complementing group 1 (XRCC1) genetic polymorphism Arg399Gln and hepatocellular carcinoma (HCC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Methods: Two investigators independently searched the Medline, Embase, CNKI and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for XRCC1 polymorphism and HCC were calculated in a fixed‐effects model (the Mantel–Haenszel method) and a random‐effects model (the DerSimonian and Laird method) when appropriate. The pooled ORs were performed for a codominant model (Gln/Gln vs. Arg/Arg, Arg/Gln vs. Arg/Arg), a dominant model (Gln/Gln+Arg/Gln vs. Arg/Arg) and a recessive model (Gln/Gln vs. Arg/Gln+Arg/Arg). Results: This meta‐analysis included 11 case–control studies, which included 2208 HCC cases and 3265 controls. Overall, the variant genotypes (Gln/Gln and Arg/Gln) of Arg399Gln were not associated with HCC risk when compared with the wild‐type Arg/Arg homozygote (Gln/Gln vs. Arg/Arg, OR=1.01, 95% CI=0.79–1.28; Arg/Gln vs. Arg/Arg, OR=1.09, 95% CI=0.81–1.45). Similarly, no associations were found in the dominant and recessive models (dominant model, OR=1.12, 95% CI=0.85–1.47; recessive model, OR=0.99, 95% CI=0.79–1.25). Limiting the analysis to the studies within Hardy–Weinberg equilibrium, the results were persistent and robust. When stratifying for ethnicity, country/region and source of controls, no evidence of a significant association was observed in any subgroup. No publication bias was found in the present study. Conclusion: No association is found between the XRCC1 polymorphism Arg399Gln and the risk of HCC.     

Prognostic importance of DNA repair gene polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> Arg399Gln and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln in lung cancer patients from India

Purpose Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. Methods In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. Results The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. Conclusions These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.     

APE1 polymorphisms are associated with colorectal cancer susceptibility in Chinese Hans

AIM: To study the association between four base excision repair gene polymorphisms and colorectal cancer risk in a Chinese population.METHODS: Two hundred forty-seven colorectal cancer (CRC) patients and three hundred cancer-free controls were enrolled in this study. Four polymorphisms (OGG1 Ser326Cys, APE1 Asp148Glu, -141T/G in the promoter region, and XRCC1 Arg399Gln) in components of the base excision repair pathway were determined in patient blood samples using polymerase chain reaction with confronting two-pair primers. The baseline information included age, gender, family history of cancer, and three behavioral factors [smoking status, alcohol consumption, and body mass index (BMI)]. χ² tests were used to assess the Hardy-Weinberg equilibrium, the distributions of baseline characteristics, and the four gene polymorphisms between the cases and controls. Multivariate logistic regression analyses were conducted to analyze the correlations between the four polymorphisms and CRC risk, adjusted by the baseline characteristics. Likelihood ratio tests were performed to analyze the gene-behavior interactions of smoking status, alcohol consumption, and BMI on polymorphisms and CRC susceptibility.RESULTS: The APE1 148 Glu/Glu genotype was significantly associated with an increased risk of colorectal cancer (OR = 2.411, 95%CI: 1.497-3.886, P < 0.001 relative to Asp/Asp genotype). There were no associations between OGG1, XRCC1, or APE1 promoter polymorphisms and CRC risk. A multivariate analysis including three behavioral factors showed that the APE1 148 Glu/Glu genotype was associated with an increased risk for CRC among both smokers and non-smokers, non-drinkers and individuals with a BMI ≥ 25 kg/m² (ORs = 2.356, 3.299, 2.654, and 2.581, respectively). The XRCC1 399 Arg/Gln genotype was associated with a decreased risk of CRC among smokers and drinkers (OR = 0.289, 95%CI: 0.152-0.548, P < 0.001, and OR = 0.327, 95%CI: 0.158-0.673, P < 0.05, respectively). The APE1 promoter polymorphism -141 T/G genotype was associated with a reduced risk of colorectal cancer among subjects with a BMI < 25 kg/m² (OR = 0.214, 95%CI: 0.069-0.660, P < 0.05 relative to T/T genotype). There were significant gene-behavior interactions between smoking status and XRCC1 Arg399Gln, as well as BMI and APE1 -141T/G polymorphism (all P < 0.05).CONCLUSION: APE1 Asp148Glu is associated with increased CRC risk and smoking alters the association between XRCC1 Arg399Gln and CRC risk in the Chinese Han population.     

A meta-analysis of XRCC1 single nucleotide polymorphism and susceptibility to gynecological malignancies

Background:Gynecological malignant tumor is a serious threat to women''s health, cervical cancer, endometrial cancer and ovarian cancer are the most common. The eponymous protein encoded by the XRCC1 (X-ray repair cross complementation 1) gene is an important functional protein in the process of single-stranded DNA damage. Non-synonymous mutations of XRCC1 gene cause amino acid sequence changes that affect protein function and DNA repair ability, and may affect the interaction with other DNA repair proteins, leading to increased risk of tumor development. Many studies have assessed the association between XRCC1 gene polymorphism and the risk of cancer in the female reproductive system, but the results have been inconclusive. In this study, the relationship between XRCC1 Arg399Gln, Arg194Trp, Arg280His single nucleotide polymorphisms and susceptibility to gynecological malignancies was further explored by meta-analysis.Methods:English database: Pubmed, Medline, Excerpta Medica Database, Cochrance, etc; Chinese database: China national knowledge infrastructure, Wanfang Database, etc. STATA14 was used for statistical analysis, such as odd ratio (OR) value, subgroup analysis, heterogeneity test, sensitivity analysis, and publication bias.Results:In gynecologic cancers, the allele frequency difference of Arg399Gln case control group was statistically significant (GvsA: P = .007). There was no significant difference in allele frequency in the Arg194Trp and Arg280His case control groups (P = .065, 0.198). In different gene models, Arg399Gln was significantly correlated with gynecologic cancers susceptibility (GGvs AA: OR 0.91; 95% confidence interval [CI], 0.85 0.98); Arg194Trp was significantly correlated with gynecologic cancers susceptibility (CCvs TT: OR 0.94; 95% CI 0.88,1.00; CCvs CT: OR 0.97; 95% CI 0.90, 1.05); Arg280His was significantly correlated with gynecologic cancers susceptibility (GGvs AA: OR 0.98; 95% CI 0.94, 1.02; GGvs GA: OR 1.00;95% CI 0.97, 1.04). In the subgroup analysis, Arg399Gln and Arg194Trp were significantly correlated with gynecologic cancers susceptibility in the Asian race (P = .000, 0.049). In the analysis of different cancer subgroups, Arg399Gln and cervical cancer susceptibility were statistically significant (P = .039). Arg194Trp and endometrial cancer susceptibility were statistically significant (P = .033, 0.001).Conclusions:XRCC1 Arg399Gln, Arg194Trp, Arg280His single nucleotide polymorphisms were associated with gynecologic cancer susceptibility. Arg399Gln genotype was statistically significant in relation to cervical cancer susceptibility. Arg194Trp genotype was statistically significant in relation to endometrial cancer susceptibility.     

Rheumatoid arthritis risk associates with DNA repair gene XRCC1 Arg399Gln polymorphism in Turkish patients

Rheumatoid arthritis (RA) is an autoinflammatory disease with a genetic background. The synoviocytes in RA shows cellular transformation with tumor-like features, and RA patients have genomic instability and relaxation of DNA repair mechanisms. The polymorphisms in BER repair pathway genes, XRCC1 and OGG1, may change the response to inflammation via altered DNA repair capacity. In this study, we aimed to investigate the relationship between the risk of RA and XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms in a group of Turkish RA patients. XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms were investigated by PCR–RFLP method in 100 RA patients and 158 healthy control subjects. The results were statistically analyzed by calculating the odds ratios (OR) and their 95% confidence intervals (95% CI) using the χ²-tests. RA patients in this study had significantly higher frequencies of XRCC1 Arg399Gln polymorphism in both homozygote (GG) (35%, OR: 7.78 [95% CI: 3.65–16.59], P < 0.001) and heterozygote (AG) forms (41%, OR: 2.17 [95% CI: 1.19–3.96], P < 0.01) and also increased frequency of 399Gln (G) allele (55%, OR:2.99 [95% CI: 1.67–5.37], P < 0.001). We conclude that XRCC1 Arg194Trp, and OGG1 Ser326Cys polymorphisms are not associated with RA; however, Arg399Gln polymorphism is a significant risk factor of RA, and carriers of 399Gln (G) allele have greater risk of RA.     

DNA repair gene XRCC1 and XPD polymorphisms and their association with coronary artery disease risks and micronucleus frequency

Coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. In this study, we investigated the effects of the XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms on the presence and the severity of CAD. We also investigated the presence of DNA damage in the peripheral lymphocytes of patients with CAD by using the micronucleus (MN) test and the effect of XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms on this damage. The study population consisted of 147 patients with angiographically documented CAD and 48 healthy controls. No association between XPD Lys751Gln or XRCC1 Arg399Gln polymorphisms and the presence or the severity of CAD was observed. On the other hand, a significantly higher frequency of MN was observed in CAD patients compared with controls (5.7 ± 1.9 vs 5.0 ± 2.1, respectively, P = 0.018). We found an elevated frequency of MN in CAD patients with the XPD 751Gln allele (Gln/Gln genotype) or the XRCC1 399Gln (Arg/Gln or Gln/Gln genotypes) allele compared with the XPD 751Lys (Lys/Lys genotype) allele or XRCC1 399 Arg (Arg /Arg genotype) allele, respectively. These preliminary results suggest that XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms may not be a significant risk factor for developing CAD. In addition, our results indicate that the MN frequency is associated with presence, but not severity, of CAD and is related to the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms, suggesting an elevated frequency of MN in CAD patients with the XPD 751Gln or XRCC1 399Gln alleles.     

XRCC1和XPD单核苷酸多态性与非小细胞肺癌铂类药物化疗敏感性的关系

目的研究X线修复交叉互补基因1（XRCC1）和着色性干皮病基因（XPD）单核苷酸多态性与老年晚期非小细胞肺癌（NSCLC）铂类药物化疗敏感性关系。方法应用聚合酶链反应结舍限制性片段长度多态性（PCR-RFLP）的方法检测81例以铂类药物为主要化疗方案的NSCLC患者XRCC1 Arg399Gln和XPD Lys751Gin基因型多态性，采用非条件Logistic回归分析不同基因型与化疗疗效的关系。结果81例患者化疗总有效率为35．8％，其中完全缓解（CR）、部分缓解（PR）、稳定（SD）和进展（PD）患者分别为0、29、31、21例。携带至少1个XRCC1 399Arg等位基因的患者化疗敏感性是携带Gln／Gln基因型患者的4.52倍（OR=4．52，95％CI=1.11—18．38）。未发现XPD Lys751Gin遗传多态与化疗敏感性相关。结论XRCC1 Arg399Gln多态可能与晚期NSCLC铂类药物化疗敏感性有关。     

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

Purpose

Genetic polymorphisms in DNA repair genes may influence variations in individual DNA repair capacity, which could be associated with the development of cancer. We detected the distributions of three single-nucleotide polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln) in DNA repair genes, and assessed the associations of these genetic polymorphisms with colon and rectal cancer susceptibility as well as evaluated the interactions of gene–gene and gene–environment in a case–control study of an Indian population.

Methods

This case–control study was conducted with 302 cases (including 59 colon and 243 rectal cancer patients) and 291 cancer-free healthy controls. Genotypes were determined by PCR–RLFP assays. The effects [odds ratios (ORs) and 95% confidence intervals (95% CIs)] of genetic polymorphisms on colorectal cancer were estimated using unconditional logistic regression.

Results

The XRCC1 399Gln allele was found to be associated with a significantly increased rectal cancer risk among men (OR = 1.65, 95% CI 1.04–2.64). Whereas the XRCC3 241Met allele showed a protective tendency against rectal cancer (OR = 0.68, 95% CI 0.46–1.02) for both men and women. Furthermore, a combination of the XRCC1 399Gln allele with XRCC3 Thr/Thr genotype and the XPD 751Gln allele demonstrated the highest rectal cancer risk (OR = 3.52, 95% CI 1.43–9.44).

Conclusions

The combined effects of putative risk alleles/genotypes for different DNA repair pathways may strengthen the susceptibility to rectal cancer.     

Identification of XRCC1 Arg399Gln and XRCC3 Thr241Met Polymorphisms in a Turkish Population and Their Association with the Risk of Chronic Lymphocytic Leukemia

DNA repair systems are essential for cellular functions. Defects due to sequence variations in DNA repair genes can lead severe failure of cell functions and causing many cancer types including leukemia. The aim of this study was to investigate the relationship between XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and susceptibility to chronic lymphocytic leukemia (CLL) in Turkish patients. In addition, genotype distribution of these polymorphisms was compared with other populations. The frequencies of Arg399Gln and Thr241Met single nucleotide polymorphisms were studied in 25 CLL patients and 30 healthy individuals. Single nucleotide polymorphisms were genotyped by PCR–RFLP method. The genotype and allele frequencies of Arg399Gln and Thr241Met polymorphisms were not statistically different between the CLL patients and control group. The allelic frequency similarities were found between Turkish and Brazilian populations for Arg399Gln polymorphism. On the other hand, similarities were found between Turkish and other Caucasian populations for Thr241Met polymorphism. Marked differences were observed between American African versus Turkish and Chinese versus Turkish populations for Arg399Gln and Thr241Met polymorphisms respectively. These results indicate that Arg399Gln and Thr241Met polymorphisms were not associated with the development of CLL in Turkish population and ethnic differences is one of the most important factor for allele frequency differences.     

Polymorphisms of DNA repair genes XRCC1 and XRCC3, interaction with environmental exposure and risk of chronic gastritis and gastric cancer

AIM: To evaluate the association between polymorphisms XRCC1 Arg194Trp and Arg399Gln and XRCC3 Thr241Met and the risk for chronic gastritis and gastric cancer, in a Southeastern Brazilian population. METHODS: Genotyping by PCR-RFLP was carried out on 202 patients with chronic gastritis (CG) and 160 patients with gastric cancer (GC), matched to 202 (CI) and 150 (C2) controls, respectively. RESULTS: No differences were observed among the studied groups with regard to the genotype distribution of XRCCl codons 194 and 399 and of XRCC3 codon 241. However, the combined analyses of the three variant alleles (194Trp, 399Gln and 241Met) showed an increased risk for chronic gastritis when compared to the GC group. Moreover, an interaction between the polymorphic alleles and demographic and environmental factors was observed in the CG and GC groups. XRCC1 194Trp was associated with smoking in the CG group, while the variant alleles XRCC1 399Gln and XRCC3 241Met were related with gender, smoking, drinking and H pylori infection in the CG and GC groups. CONCLUSION: Our results showed no evidence of a rela-tionship between the polymorphisms XRCCl Argl94Trp and Arg399Gln and XRCC3 Thr241Met and the risk of chronic gastritis and gastric cancer in the Brazilian population, but the combined effect of these variants may interact to increase the risk for chronic gastritis, considered a premalignant lesion. Our data also indicate a gene-environment interaction in the susceptibility to chronic gastritis and gastric cancer.     

The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia

Polymorphisms in several DNA repair genes have been described. These polymorphisms may affect DNA repair capacity and modulate cancer susceptibility by means of gene-environment interactions. We investigated DNA repair capacity and its association with acute myeloblastic leukemia (AML). We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD. We also assessed the incidence of a functional polymorphism in the NQO1 gene, which is involved in protection of cells from oxidative damage. We genotyped the polymorphisms by using polymerase chain reaction-restriction fragment-length polymorphism analysis in 134 patients with de novo AML, 34 with therapy-related AML (t-AML), and 178 controls. The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls. However, the distribution of the XRCC1 Arg399Gln genotypes was significantly different when comparing the t-AML and control groups (chi(2), P =.03). The presence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in controls compared with patients with t-AML (odds ratio 0.44; 95% confidence interval, 0.20-0.93). We found no interactions between the XRCC1 or XRCC3 and NQO1 genotypes. We also found no differences in the distribution of the XPD Lys751Gln or XRCC1 Arg194Trp genotypes. Our data provide evidence of a protective effect against AML in individuals with at least one copy of the variant XRCC1 399Gln allele compared with those homozygous for the common allele.     

原发性肝癌患者DNA损伤修复酶基因多态性分析

目的探讨DNA损伤修复酶基因多态性与原发性肝癌发生发展的关系。方法 PCR-RFLP法检测150例肝癌患者（肝癌组）和150例健康体检者（对照组）DNA损伤修复酶基因的表型,并进行比较。结果肝癌组XRCC1 Arg399Gln位点野生型的比率明显低于对照组（P〈0.05）;XRCC1（Arg194Trp、Arg280His）、hOGG1Ser326Cys位点多态性型别在两组中出现的频率相近（P〉0.05）;各基因位点不同表型者的尿8-羟基脱氧鸟苷（8-OHdG）水平相比,P均〉0.05。结论 DNA修复酶基因多态性与肝癌的发生发展无明确的相关关系。     

The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China.

AIM: High incidence rates of hepatocellular carcinoma (HCC) in Guangxi, China, are primarily due to heavy aflatoxin B1 (AFB1) exposure via corn and groundnut consumption. This study was designed to examine the polymorphisms associated of three carcinogen-metabolizing genes (namely: GSTM1, GSTT1, and HYL1*2) and one DNA-repair gene (namely: XRCC1), and investigate their role as susceptibility markers for HCC. METHODS: We conducted a case-control study including 257 cases of cancer and 649 hospital-based age, sex, ethnicity, and hepatitis B virus infection-matched controls to examine the role of genetic polymorphisms of four genes (GSTM1, GSTT1, HYL1*2, and XRCC1) in the context of HCC risk for the Guangxi population. Genomic DNA isolated from 2ml whole blood was used to genotype GSTM1, GSTT1, HYL1*2, and XRCC1 by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: GSTT1-null genotype was not significantly associated with the risk of HCC, but GSTM1-null genotype [adjusted odds ratio (OR)=2.29, 95% confidence interval (CI)=1.59-3.31], HYL1*2 genotypes with 113 His allele (namely: YH/HH, adjusted OR=2.55, CI=1.78-3.65), and XRCC1 genotypes with 399 Gln allele (namely: AG/GG, adjusted OR=2.47, CI=1.72-3.54) increased the HCC risk. Compared with those individuals who did not express any putative risk genotypes as reference (OR=1), individuals featuring all of the putative risk genotypes [GSTM1-null, HYL1*2-YH/HH, and XRCC1-AG/GG] did experience a significantly greater cancer risk (adjusted OR=10.83, CI=5.44-21.59, P(interaction)<0.01). Additionally, the risk of HCC did appear to differ more significantly among individuals featuring risk genotypes and high-level or long-term AFB1 exposure, whose adjusted ORs (CIs) were 52.44 (17.51-157.08) and 326.93 (38.58-2770.52), respectively. CONCLUSIONS: The results suggest that carcinogen metabolism and DNA-repair pathways may simultaneously modulate the risk of HCC for Guangxi population, and, particularly for these having high-level or long-term AFB1 exposure.     

XRCC1 Arg399Gln, Arg194Trp, and Arg280His Polymorphisms in Esophageal Cancer Risk: A Meta-Analysis

Background

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair.

Aim

To elucidate the role of XRCC1 Arg399Gln, Arg194Trp and Arg280His genotypes in esophageal cancer risk, all available studies were considered in the present meta-analysis.

Methods

Eligible studies were identified by searching several electronic databases for relevant reports published before June 2012.

Results

According to the inclusion criteria and exclusion criteria, a total of 21 eligible studies were included in the pooled analyses. Among the 21 studies, 18 focused on Arg399Gln polymorphism, 11 described the Arg194Trp, and 4 articles investigated on Arg280His. Our analysis suggested that there was no evidence of significant association between XRCC1 Arg399Gln polymorphism and esophageal cancer risk in any genetic model. In the stratified analysis by ethnicity for Arg399Gln polymorphism and esophageal cancer, the results showed that Arg399Gln polymorphism was not associated with esophageal cancer risk. Only 4 studies analyzed the relationship between XRCC1 Arg280His polymorphism and the risk of esophageal cancer. The Arg/His and His/His genotypes were not significantly associated with increased risk of EC. A similar negative association was maintained in dominant and recessive models. However, for XRCC1 Arg194Trp polymorphism, our study showed individuals carrying the variant genotype Trp/Trp had a significant increased risk of esophageal cancer (OR = 1.295, 95 % CI 1.053–1.591, P = 0.014). In addition, increased associations were found in recessive model (OR = 1.332, 95 % CI 1.093–1.624, P = 0.005).

Conclusions

Our meta-analysis suggested that Arg194Trp Trp allele might act as a risk allele in its association with esophageal cancer.     

X线损伤交叉互补基因1多态性与结直肠癌易感性研究

目的 探讨DNA修复酶X线损伤交叉互补基因1(XRCC1 )外显子三个位点的基因多态性(Arg194Trp 、Arg280His、Arg399Gln)与结直肠癌(CRC)发病风险的关系.方法 以聚合酶链反应和限制性片段长度多态性(PCR-RFLP)分析方法,采用病例-对照研究,对250例CRC患者(病例组,其中结肠癌128例,直肠癌122例)和213名健康人(对照组)的XRCC1基因三个位点的多态性进行了检测,采用SPSS 11.0软件包统计分析各位点的基因型分布和等位基因频率.结果 XRCC1基因194和399二个位点的各基因型频率在两组间分布差异均无统计学意义(P值均>0.05),但病例组XRCC1基因280 Arg/His基因型频率较对照组显著增高(校正后OR=1.66,95%CI:1.01～2.73,P=0.047).在直肠癌患者组中,280Arg/His基因型频率较对照组显著增高(OR=1.82,95%CI:1.02～3.27),携等位基因280His(Arg280His +His280His)的CRC患者的频率显著高于其在对照组中的频率(校正后OR=1.85,95%CI:1.06～3.22),而在结肠癌患者中风险系数相对较低且差异无统计学意义(校正后OR=1.31,95%CI:0.74～2.35).结论 XRCC1 Arg194Trp和 Arg399Gln基因多态性与结肠癌易感性无关,但280Arg/His基因型能增加CRC易感性,等位基因280His是直肠癌风险因素.

Abstract：

Objective To investigate the correlation between three gene locus polymorphisms of X-ray repair cross-complementary protein 1 (XRCC1) exon (Arg194Trp, Arg280His and Arg399Gln) and the risk of colorectal cancer (CRC). Methods A case-control study was performed in 250 CRC patients (case group, 128 colon cancer patients and 122 rectal cancer patients) and 213 healthy individuals (control group). The three gene locus polymorphism of XRCC1 was tested by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The genotype distribution and allele frequency of each locus was analyzed with SPSS 10.0 software. Results There was no significant difference in allele frequency of XRCC1 at 194 and 399 loci (P > 0.05). However, the 280 Arg/His allele frequency of XRCC1 was higher in case group than that in control group (OR=1.66,95%CI:1.01~2.73,P=0.047). The 280Arg/His allele frequency was higher in rectal cancer group than that in control group (OR =1.82,95%CI:1.02~3.27). The frequency of 280His allele (Arg280His and His280His) was higher in case group than that in control group (OR=1.85,95%CI:1.06~3.22). However, it was a relative low risk factor of colon cancer and there was no significant difference between colon cancer group and control group (OR=1.85, 95%CI:1.06~3.22). Conclusions There was no correlation between XRCC1 Arg194Trp and Arg399Gln polymorpohisms and the risk of CRC. However, 280Arg/His genotype may increase the risk of CRC, and 280His allele is a risk factor of rectal cancer.     

人类XRCC1-399单核苷酸多态性与原发性肝细胞癌的相关研究

目的以病例-对照研究方式探讨人类DNA修复基因XRCC1-399单核苷酸多态性(SNP)与HBV感染者的原发性肝细胞癌(HCC)的发生关系。方法72例HCC患者经病理检查证实,根据地缘、性别、年龄,按1：1～2比例匹配137例非HCC对照者。采用聚合酶链反应一限制片段长度多态性(PCR-RFLP)技术检测受试者XRCC1-399位SNP。结果(1)XRCC1-399SNP和年龄均与HCC的发生无关,但在XRCC1-399Arg／Arg受试者中,HCC的发生与年龄呈负相关(P=0．028);(2)HBV感染是HCC发生的肯定因素(P=0．007);在XRCC1-399Gln／Gln或Arg／Gln受试者中,伴HBV感染者HCC发生率(25．7％)远高于不伴HBV感染者(5．3％,P=0．047);(3)XRCC1-399Arg／Arg受试者HBV感染率与Gln/Gln或Arg／Gln受试者近似(36．6％对38．0％,P=0．052)。结论(1)XRCC1-399Arg／Arg可能具有潜在抵抗HCC发生的作用;(2)XRCC1-399Gln／Gln或Arg／Gln联合HBV感染是HCC发生的高危因素。     

Possible association of the X-ray cross complementing gene 1 (XRCC1) Arg280His polymorphism as a risk for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the invasion of synovial cells into cartilage and bone, exhibiting certain features of transformed cells. To examine whether retardation of DNA repair pathway of oxidative damage is a possible mechanism in altered phenotypes of these cells, we analyzed SNPs of the base excision repair (BER) protein, X-ray repair cross complementing gene 1 (XRCC1), among RA patients. Genomic DNA was extracted from blood cells of 40 RA patients and SNPs of the three allele of the XRCC1 coding region (codons 194, 280 and 399) were determined by PCR, followed by sequencing. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased RA risk (odds ratio 13; 95% confidence interval 1.1–147) after adjustment for smoking. These data provide evidence for the first time that BER, which is involved in the recovery from oxidative damage, may correlate with RA.