Single nucleotide polymorphisms in base-excision repair genes hOGG1, APE1 and XRCC1 do not alter risk of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a poorly understood etiology. There is considerable evidence that oxidative stress occurs in AD and increased DNA damage has been found in brain tissues and leukocytes of AD patients. Base excision repair (BER) is the major pathway responsible for removing oxidative DNA damage. Polymorphisms in DNA-repair genes have been associated with the increased risk of several age-related disorders including various types of cancer and could also be related to the etiology of AD. We conducted a case-control study including 91 patients with AD and age- and sex-matched 93 control subjects to examine the role of single nucleotide polymorphisms of BER genes, hOGG1 (Ser326Cys), APE1 (Asp148Glu) and XRCC1 (Arg280His and Arg399Gln) as a risk factor for AD. The frequencies of the hOGG1-Ser326Cys, APE1-Asp148Glu and XRCC1-Arg280His and XRCC1-Arg399Gln variant alleles in our control group were 0.23, 0.31, 0.10 and 0.33, respectively. No significant association was observed between the variant alleles of hOGG1-Ser326Cys (OR=1.32, 95% CI=0.83-2.11), APE1-Asp148Glu (OR=1.08, 95% CI=0.70-1.68), XRCC1-Arg280His (OR=0.53, 95% CI=0.24-1.14) and XRCC1-Arg399Gln (OR=1.05, 95% CI=0.68-1.63) and AD. Our results suggest that the polymorphic variants of these BER genes are not independent risk factors for AD.     

DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span

To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20-75 years. SNPs examined included PolB(Pro242Arg), hOGG1(Ser326Cys), MutYH (Met22Val), MutYH(His324Gln), APE1(Gln51His), APE1(Glu148Asp), XRCC1(Lys298Asn), XRCC1(Arg7Leu), NEIL1(Asp252Asn), and NEIL2(Arg257Leu). XRCC1(Arg7Leu) and PolB(Pro242Arg) were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1(Ser326Cys) (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH(His324Gln) (His/Gln37%/Gln/Gln 6.0%) and APE1(Glu148Asp) (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH(Met22Val), APE1(Gln51His) and NEIL2(Arg257Leu) occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1(Ser326Cys) and APE1(Gln51His) had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH(His324Gln), MutYH(Met22Val), PolB(Pro242Arg) and NEIL2(Arg257Leu) were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.     

XRCC1、hOGG1基因多态性与喉癌遗传易感性的关系

目的 探讨X线修复交叉互补组1基因(X-ray repair cross complementing group 1,XRCC1)、8-羟基鸟嘌呤修复酶基因(human 8-oxoguanine glycosylase I,hOGG1)多态性与喉癌遗传易感性的关系.方法 采用病例-对照设计,应用聚合酶链反应-限制性片段长度多态性分析法检测了72例经病理确诊的喉癌患者和随机抽样的72例无肿瘤、无遗传病对照者XRCC1-Arg399Gln、hOGG1-Ser326Cys多态性.结果 病例组XRCC1第399位密码子杂合型(Arg/Gln)及突变型(Gln/Gln)和hOGG1第326位密码子杂合型(Ser/Cys)及突变型(Cys/Cys)分布频率均高于对照组(P＜0.05),与携带XRCC1-399野生型(Arg/Arg)、hOGG1-326野生型(Ser/Ser)个体相比,携带该基因型的个体喉癌的发病风险分别升高了3.37和2.54倍.交互作用分析显示,吸烟组与不吸烟组相比,携带XRCC1、hOGG1各基因型的个体的喉癌发病风险差异未发现存在统计学意义(xH12=0.15,xH22=0.28,P＞0.05).结论 XRCC1-399位点Arg→Gln和hOGG1-326位点Ser→Cys的氨基酸替换可能导致喉癌的发病风险增加,XRCC1-Arg399Gln、hOGG1-Ser326Cys多态性可能与喉癌的遗传易感性有关.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

DNA repair gene XRCC1 and XPD polymorphisms and the risk of idiopathic azoospermia in a Chinese population

Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and further influence the risk of developing cancer. However, little information is available on these polymorphisms in infertility. To investigate whether polymorphisms in DNA repair genes, X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD), alone or in combination, are associated with the risk of developing idiopathic azoospermia, the genotype and allele frequencies of three observed polymorphisms (XRCC1 Arg194Trp and Arg399Gln, and XPD Lys751Gln) were examined by polymerase chain reaction-restriction fragment length polymorphism based on a Chinese population consisting of 171 idiopathic azoospermia patients and 247 normal-spermatogenesis fertile controls. Associations between the polymorphisms and the idiopathic azoospermia risk were estimated by logistic regression, and the Statistical analysis system was used to test the gene-gene joint effects. All observed polymorphisms were in agreement with Hardy-Weinberg equilibrium. The XPD 751Gln allele seemed to be a risk allele for azoospermia, with a frequency of 11.40% in the cases and 5.67% in the controls (p=0.004). Compared with the Lys/Lys genotype, the XPD 751 Lys/ increased 5.100- or 3.064-fold, respectively, when combined with the XRCC1 194 Arg/Arg or 399 Arg/Arg genotype. In conclusion, our study provided the first evidence that the XPD and XRCC1 polymorphisms contributed to the risk of developing idiopathic azoospermia in a selected Chinese population.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

Radio-adaptive response,individual radio-sensitivity and correlation of base excision repair gene polymorphism (hOGG1, APE1, XRCC1, and LIGASE1) in human peripheral blood mononuclear cells exposed to gamma radiation

Radio-adaptive response (RAR) is a biological mechanism, where cells primed with a low dose exhibit reduced DNA damage with a high challenging dose. Single nucleotide polymorphisms (SNPs) of DNA repair genes including base excision repair (BER) pathway are known to be associated with radio-sensitivity but involvement in RAR is not yet understood. In the present study, attempt was made to correlate genotype frequencies of four BER SNPs [hOGG1(Ser326Cys), XRCC1(Arg399Gln), APE1(Asp148Glu) and LIGASE1(A/C)] with DNA damage, repair and mRNA expression level among 20 healthy donors (12 adaptive and 8 nonadaptive). Our results revealed that LIGASE1 (p = .002) showed significant correlation with DNA damage and mRNA expression level with increasing dose. hOGG1 (Ser326Cys), XRCC1 (Arg399Gln) and LIGASE1(A/C) polymorphisms showed significant difference with DNA damage (%T) and mRNA expression profile in primed cells among adaptive donors. In conclusion, BER gene polymorphisms play important role in identifying donors with radio-sensitivity and RAR in human cells.     

XRCC1 codon 399 and ERCC2 codon 751 polymorphism, smoking, and drinking and risk of esophageal squamous cell carcinoma in a North Indian population

XRCC1 (X-ray cross-complementing group 1) codon 399 and ERCC2 (excision repair cross-complementing group 2) codon 751 polymorphisms were studied in esophageal squamous cell carcinoma (ESQCC) in a North Indian population. Peripheral blood samples of 120 cases and 160 age-and-gender matching controls were collected from North India and the two polymorphisms were studied by means of polymerase chain reaction-restriction fragment length polymorphism techniques. The data were analyzed with a logistic regression model. The XRCC1 codon 399 Gln/Gln genotype was significantly associated with reduced risk of ESQCC (OR = 0.31, 95% CI = 0.12-0.78, P = 0.01). In smokers, the XRCC1 Arg/Gln genotype was marginally and statistically nonsignificantly (OR = 1.5) associated with increased risk of this cancer. In drinkers, the XRCC1 Gln/Gln genotype was significantly protective (OR = 0.06, 95% CI = 0.007-0.605, P = 0.03), whereas ERCC2 (Lys/Gln-Gln/Gln) was marginally associated with increased risk (OR = 2.1, 95% CI = 0.46-9.44). Upon analysis of gene-gene interaction, a relationship was observed, although statistically nonsignificant, between combined genotypes of XRCC1 (Arg/Gln-Gln/Gln)-ERCC2 Gln/Gln (OR = 0.33, 95% CI = 0.09-1.16) and XRCC1 (Gln/Gln)-ERCC2 (Lys/Gln) (OR = 0.36, 95% CI = 0.11-1.17) and reduced risk of ESQCC in the North Indian population. These observations suggest that the Gln/Gln genotype of XRCC1 might play an important role in DNA repair in ESQCC.     

北京地区汉族人群DNA修复基因XPD单核苷酸多态性与肺癌及食管癌风险的研究

目的：研究核苷酸切除修复基因XPD单核苷酸多态性与北京地区汉族人群肺癌及食管癌风险的关系。方法：采用以医院患者为基础的病例－对照研究方法，包括正常对照383人，肺癌患者351例，食管癌患者325例。以聚合酶链反应－限制性片段长度多态性方法分析了XPD基因Asp312 Asn和Lys751Gln多态性，比较不同基因型与肺癌及食管癌风险的关系，并探讨吸烟与基因多态交互作用对患癌风险的影响。结果：与携带312 Asp/Asp基因型者比较，携带至少1个312Asn等位基因者（即Asp/Asn和Asn/Asn基因型）罹患肺鳞癌的风险增加1．8倍（95％CI1．10－2．93），而与肺腺癌无关（校正的比值比为1．07，95％CI0．55－2．08）。分层分析显示，风险型等位基因312Asn和751Gln与吸烟有明显的交互作用。吸烟剂量≥29包／年且携带312Asn或751Gln者罹患肺鳞癌的风险最高，校正的比值比分别为12．44（95％CI4．97－31．17）和10．74（95％CI4．51－25．57）。XPD基因Asp312Asn和Lys751Gln多态与食管鳞癌风险无关。结论：XPD基因Asp312Asn和Lys751Gln多态是地区汉族人群肺鳞癌遗传易感因素，而与肺腺癌以及食管鳞癌风险无关，可能反映了不同组织学类型肺癌以及肺癌和食管癌之间的病因学差异。     

Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis

Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p=0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06-2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p=0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09-4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16-4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis.     

hOGG1(326), XRCC1(399) and XRCC3(241) polymorphisms influence micronucleus frequencies in human lymphocytes in vivo

A pooled analysis of five biomonitoring studies was performed to assess the influence of hOGG1(326), XRCC1(399) and XRCC3(241) gene polymorphisms on micronuclei (MN) frequency in human peripheral blood lymphocytes, as measured by the ex vivo/in vitro cytokinesis-block micronucleus (CBMN) assay. Each study addressed a type of occupational exposure potentially able to induce DNA strand breakage (styrene, ionising radiation, cobalt/hard metal, welding fumes and inorganic arsenite compounds), and therefore MN, as a result of base excision repair and double-strand break repair deficiencies. The effect of genotype, age, exposure to genotoxic agents and smoking habit on MN induction was determined using Poisson regression analysis in 171 occupationally exposed male workers and in 132 non-exposed male referents. The analysis of genotype-genotype, genotype-smoking and genotype-exposure interactions by linear combinations of parameters showed significantly higher MN frequencies in the following subsets: (i) occupationally exposed workers carrying either the Thr/Thr or the Thr/Met XRCC3(241) genotypes compared to their referent counterparts (P < 0.001) and (ii) carriers of the Met/Met XRCC3(241) genotype compared to Thr/Thr XRCC3(241) carriers, as far as they are non-exposed and bear the variant (Ser/Cys or Cys/Cys) hOGG1(326) genotype (P < 0.01). Significantly lower MN frequencies were observed in carriers of the variant hOGG1(326) genotype compared to Ser/Ser hOGG1(326) carriers in the subgroup of non-smokers with Thr/Thr XRCC3(241) genotype (P < 0.01). Stratified analysis by occupational exposure showed a significant MN increase with smoking in occupationally exposed carriers of the Arg/Gln XRCC1(399)genotype (P < 0.001). In contrast, a significant MN decrease with smoking was observed in referents carrying the Ser/Ser hOGG1(326) genotype (P < 0.01). These findings provide evidence that the combination of different DNA repair genes and their interaction with environmental genotoxic agents may modulate MN induction. Understanding the complexity of the relationships between exposure, DNA repair and MN frequencies require larger scale studies and complementary biomarkers.     

Influence of DNA repair gene polymorphisms on the initial repair of MMS-induced DNA damage in human lymphocytes as measured by the alkaline comet assay

We have applied the alkaline comet assay to study the functional impact of gene polymorphisms in base excision repair (APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg399Gln) and homologous recombination repair (XRCC3 Thr241Met, NBS1 Glu185Gln), two pathways that play crucial roles in the repair of DNA damage induced by methylmethane sulphonate (MMS). We also examined the effect of polymorphisms in mismatch repair (MLH1 -93 A/G) and nucleotide excision repair (XPD Lys751Gln) as putative negative controls based on the limited roles of these pathways in MMS-induced repair. Phytohemagglutinin-stimulated peripheral lymphocytes from 52 healthy individuals were treated with MMS and allowed to repair for 0, 15, 40, or 120 min after a 6-min washing step. DNA damage was measured as a pseudo-percentage score (comparable to % tail DNA) converted from a total visual score calculated from the distribution of cells with different degrees of damage (normal, mild, moderate and severe). The repair was faster at the beginning of the observation period than towards the end, and was not complete after 2 hr. Presence of the APEX1 148Asp, XRCC3 241Met or NBS1 185Gln alleles were significantly associated with a high pseudo-percentage score (above median) at early time points, with the APEX1 effect being most prolonged (up to 40 min after washing, odds ratio 5.6, 95% confidence interval 2.0-15.5). No significant effects were seen with the XRCC1 Arg194Trp, XRCC1 Arg399Gln, MLH1 -93A/G and XPD Lys751Gln polymorphisms. Our results provide evidence for the functional nature of the variant alleles studied in the APEX1, XRCC3, and NBS1 genes.     

Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: a meta-analysis

Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, can result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide excision repair pathway genes, focusing on xeroderma pigmentosum group A (XPA), excision repair cross complementing group 1 (ERCC1), ERCC2/XPD, ERCC4/XPF and ERCC5/XPG. We found an increased risk of lung cancer among subjects carrying the ERCC2 751Gln/Gln genotype (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.14 - 1.49). We found a protective effect of the XPA 23G/G genotype (OR = 0.75, 95% CI = 0.59 - 0.95). Considering the data available, it can be conjectured that if there is any risk association between a single SNP and lung cancer, the risk fluctuation will probably be minimal. Advances in the identification of new polymorphisms and in high-throughput genotyping techniques will facilitate the analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples.     

Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors

The DNA repair proteins XPD and XRCC1 are involved in the nucleotide and base excision repair of DNA lesions induced by many tobacco and environmental carcinogens. Common variant alleles at the XPD (312Asn, 751Gln) and XRCC1 (399Gln) loci have been identified and associated with increased risk for lung cancer. We therefore investigated a possible effect of these variant alleles on the frequency and spectrum of p53 mutations in the tumors of 97 Swedish lung cancer patients (56 never-smokers and 41 age-, gender-, and hospital-matched ever-smokers). The p53 gene was mutated in 4 never-smokers (7%) and 11 ever-smokers (27%). Smoking-related transversion-type mutations predominated over transitions among smokers (8:3), but not among never-smokers (1:3). None of the variant alleles altered the overall frequency of p53 mutation. Transversions, however, were marginally increased among patients with at least one XPD variant allele compared with patients who were wild-type homozygotes (73% vs. 25% for the Asp312Asn polymorphism, P = 0.095; 78% vs. 33% for Lys751Gln, P = 0.085). Five of six women or six of seven smokers who carried at least one XPD 751Gln allele had p53 transversion. The XRCC1 variant allele did not show any effect on the p53 mutation. We conclude that the XPD variant alleles may be associated with an increased frequency of smoking-related p53 mutations in lung tumors, presumably due to reduced DNA repair proficiency.     

Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations

We evaluated the influence of several DNA repair gene polymorphisms on the frequency of chromosomal aberrations (CAs) analyzed in peripheral lymphocytes, using the fluorescence in situ hybridization technique. The CA data were obtained from an earlier study of 84 healthy nonsmokers (48 women and 36 men) carefully characterized for indoor radon exposure. The frequency of translocations showed a wide interindividual variability, which was only partly explained by age. To investigate the potential role of DNA repair polymorphisms in this variation, genotypes of DNA repair genes OGG1 (codon 326), XPD (codon 751), XRCC1 (X-ray repair cross-complementing group 1) (codons 194, 280, and 399), and XRCC3 (X-ray repair cross-complementing group 3) (codon 241) were determined from leukocyte DNA using polymerase chain reaction-based methods. Negative binomial regression models were applied to evaluate the effect of the polymorphisms and other factors (age, gender, radon exposure, and medical exposure) on the frequency of CAs. No interactions between genotypes and radon, medical exposure, or gender were found. Carriers of the XRCC1 codon 280His variant allele had a two-fold increase (frequency ratio [FR] = 2.01, 95% confidence interval [CI] = 1.01-3.98; P = 0.046) in unstable exchanges (dicentrics and ring chromosomes). In addition, the XRCC3 codon 241 homozygous variant genotype (Met/Met) was associated with an increase (FR = 1.70, 95% CI = 1.06-2.74; P = 0.028) in two-way translocations when age was taken into account in the analysis. Our data suggest that the XRCC1 280His and XRCC3 241Met alleles affect individual CA levels, most probably via influencing the DNA repair phenotype.     

Polymorphisms in the thymidylate synthase promoter and the DNA repair genes XRCC1 and XPD in a Brazilian population

Polymorphisms in genes responsible for maintaining genomic integrity are potential modifiers of disease risk. Since considerable interindividual and interethnic variation in DNA repair capacity has been associated with polymorphic alleles, we evaluated the frequency of the 2R/3R variants in the TS promoter, Arg194Trp and Arg399Gln in the XRCC1 gene, and Asp312Asn and Lys751Gln in the XPD gene in 364 healthy individuals from a Brazilian population separated by ethnicity (European ancestry and African ancestry). The genotypes were determined by PCR (TS) or by PCR-RFLP (XRCC1 and XPD). The frequency of the TS 3R allele was 0.56 for whites and 0.51 for nonwhites. In the case of the XRCC1 MspI polymorphism, the allele frequencies were 0.09 for 194Trp in both nonwhites and whites and 0.27 and 0.28 for 399Gln in nonwhites and whites, respectively. For the XPD 312Asn allele, we found a frequency of 0.25 in white individuals, which was significantly different (P = 0.025) from that seen in nonwhites (0.15). Similarly, the 751Gln polymorphic allele of the XPD gene was significantly more frequent (P < 0.002) in whites (0.30) than in nonwhites (0.20). The genotype frequencies were within Hardy-Weinberg equilibrium. We concluded that the genotype and allele frequencies of XPD gene polymorphism differed between white and nonwhite Brazilians, and that the frequencies of the XPD 312Asn and XRCC1 399Gln alleles in this Brazilian population showed ethnic variability when compared with those observed in other populations.     

DNA修复基因hOGG1多态与食管癌遗传易感性

目的：研究修复８－羟基鸟嘌呤的ｈＯＧＧ１基因Ｓｅｒ３２６Ｃｙｓ多态与中国人食管癌易感性的关系。方法：采用病例－对照分子流行病学方法,以ＰＣＲ－单链构象多态（ｓｉｎｇｌｅ ｓｔｒａｎｄ ｃｏｎｆｏｒｍａｔｉｏｎ ｐｏｌｙｍｏｒｐｈｉｓｍ,ＳＳＣＰ）技术,分析了２０１名正常对照和１９６例食管癌患者ｈＯＧＧ１基因第３２６位Ｓｅｒ／Ｓｅｒ、Ｓｅｒ／Ｃｙｓ和Ｃｙｓ／Ｃｙｓ基因型分布,并比较不同基因型与食管癌风险的关系。结果：正常人群的Ｓｅｒ／Ｓｅｒ、Ｓｅｒ／Ｃｙｓ和Ｃｙｓ／Ｃｙｓ基因型频率分别为３３．８％、５２．８％和１３．４％,而食管癌病例组则分别为３９．８％、３８．８％和２１．４％。虽然两组人群的Ｃｙｓ等位基因频率基本相同（３９．８％４０．８％）,但食管癌病例组的Ｃｙｓ／Ｃｙｓ基因型频率显著高于对照组（Ｐ＜０．０５）     

Interaction between Polymorphisms of DNA Repair Genes Significantly Modulated Bladder Cancer Risk

DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.