APE1 Asp148Glu Polymorphism Research Articles

The role of the APE1 Asp148Glu polymorphism on the risk of acute myeloid leukemia in Iraqi patients

ابيضاض الدم النخاعي الحاد هو أكثر أنواع امراض الدم الخبيثة شيوعًا عند البالغين. يعد انتشار الخلايا الطافرة الغير مسيطر عليها للأسلاف النخاعية الغير متمايزة سمة مميزة لهذا المرض. يمكن إصلاح تلف الحمض النووي عن طريق مجموعة متنوعة من الأنظمة الأنزيمية الموجودة في الخلايا حقيقية النواة. تتشكل الخلايا الطافرة عندما لا يمكن إصلاح تلف الحمض النووي بواسطة آليات إصلاح الخلية. إحدى آليات إصلاح الحمض النووي هي مسار إصلاح استئصال القاعدة ، التي تكون المسئولة عن تصحيح الأضرار الصغيرة الناتجة عن التلف ألتأكسدي أو والقلوية أو المثيلة. اشتملت الدراسة على 70 مريضًا مصابًا بسرطان الدم النخاعي الحاد - 37 أنثى و 33 ذكرًا - بالإضافة إلى 30 فردًا سليمًا كمجموعة سيطرة. تم استخدام مجموعة استخلاص الحمض النووي gSYNCTM لاستخراج الحمض النووي من عينات الدم الكاملة من مجموعات الدراسة. تم استخدام طريقة PCR-RFLP لتحديد تعدد الأشكال Asp148 Glu للجين APE1 في التحليل الجيني ، تبين أن الزيادة في النمط الجيني T/T وأليل T في تعدد الأشكال في كودون APE1 148 يلعب دورًا وقائيًا في مرض ابيضاض الدم النخاعي الحادAML ، وأن الزيادة في النمط الجيني G / G يمكن أن تترافق مع خطر الإصابة بسرطان الدم الحاد. . أظهرت النتائج أن النمط الجيني المتغاير لجين APE1 ، Asp 148 Glu (T / G) وأليل G كانت أعلى بشكل ملحوظ (P <0.05) في مرضى AML مقارنة بمجموعة السيطرة . في تسلسل المنطقة التي تم دراستها ، وجد أن هناك موقعًا للتغاير يقع بين GATC و GAGC ، حيث يمثل التغيير في النيوكليوتيدات T إلى G موقع تقييد الإنزيم القاطع. حيث ارتبط النمط الجيني متعدد الأشكال 148 Glu> Asp من جين APE1 مع تطور AML في المرضى العراقيين. أثبتت الدراسة أن حاملي النمط الجيني T / T لديهم مخاطر أقل لتطور مرض ابيضاض الدم النخاعي الحادAML ، في حين أن حاملي الأليلات G لديهم مخاطر متزايدة.

ASSOCIATION BETWEEN APE1 GENE AND LUNG CANCER IN IRAQI POPULATION

The aim: To find association between ape1 gene and lung cancer in Iraqi population. Materials and methods: This study included forty patients with lung cancer and forty people of control group, ranging in age from 40 to 65 years old. Results: The results of (Asp/Glu) genotype showed a significant (p=<0.01) higher frequency in patients than in control group carrying the (Asp/Asp). Conclusions: APE1 Asp148Glu polymorphism may bear a risk for development of the lung cancer in Iraqi patients, and the Asp/Glu genotype contributed to more often predisposal of the disease by playing an important role as increased activity of gene as a result of APE1 Asp148Glu (rs1130409) polymorphism, while Asp/Asp genotype may have a protective action against this disease.

Polymorphisms in DNA repair genes increase the risk for type 2 diabetes mellitus and hypertension.

We investigated the effect of polymorphisms in four DNA repair genes, viz. RAD18 Arg302Gln (G>A) (rs373572), XPD Asp312Asn (G>A) (rs1799793), APE1 Asp148Glu (T>G) (rs3136820), and OGG1 Ser326Cys (C>G) (rs1052133) on the risk for type 2 diabetes mellitus (T2DM) and hypertension (HT) in association with smoking, tobacco chewing, and alcohol consumption in a population from Northeast India. The study subjects were comprised of 70 patients suffering from both T2DM and HT and 83 healthy controls. Genotyping was performed using ARMS-PCR for XPD Asp312Asn (G>A) and PCR-CTPP for RAD18 Arg302Gln (G>A), APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G). The RAD18 Gln/Gln genotype was found to significantly increase the risk for T2DM and HT by 30 fold. Significant high risk was observed for individuals with XPD Asn/Asn-RAD18 Arg/Gln genotypes. Smoking was found to be the single most important independent risk factor for T2DM and HT. This study concludes that RAD18 Arg302Gln and XPD Asp312Asn polymorphisms might increase the risk for T2DM and HT in association with smoking, tobacco chewing, and/or alcohol consumption, while APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G) polymorphisms do not contribute to such risk.

Association between polymorphisms of DNA repair genes and risk of type 2 diabetes mellitus in the Turkish population

Abstract Objectives DNA repair mechanisms work insufficiently in T2DM patients and hyperglycemia seen in diabetes disturbs the oxidant-antioxidant balance thus cause oxidative damage on DNA. The effects of the DNA repair genes’ have not yet been investigated on diabetes. The aim of this study was to investigate the association between APE1 Asp148Glu and XPG Asp1104His polymorphisms with T2DM in the Turkish population. Material and methods Sixty-five T2DM patients and 54 healthy individuals were included to this study as control. The polymerase chain reaction-restriction fragment length polymorphism techniques were used. Results When the study groups were compared, serum HDL-cholesterol levels were found statistically elevated in the controls. Once the APE1 Asp148Glu polymorphism distribution between the patient and control groups was investigated, the Glu/Glu genotype ratio was found significantly higher in the control group. Furthermore, the Asp/Glu genotype and the Asp allele prevalences were observed to be higher in the patient group. Also, patients with the Asp/Asp genotype had higher serum HDL-cholesterol levels than the others. Conclusion Despite the small number of subjects included, it could be interpreted that the Glu allele of the APE1 Asp148Glu polymorphism might be protective against and the Asp allele may be contributing to the development of diabetes.

Common polymorphisms of thehOGG1, APE1andXRCC1genes correlate with the susceptibility and clinicopathological features of primary angle-closure glaucoma

The present case study aims to elucidate the correlation between the human 8-hydroxyguanineglycosylase (hOGG1), APE1 and X-ray repair cross-complementing gene 1 (XRCC1) gene polymorphisms to the susceptibility and clinicopathological features of primary angle closure glaucoma (PACG) in a Chinese Han population. Blood samples were obtained from 258 PACG patients (case group) and 272 healthy volunteers (control group). PCR with sequence-specific primer (PCR-SSP) was used to determine the allele frequencies and genotype distributions of the hOGG1, APE1 and XRCC1 genes. The risk factors of PACG were determined using logistic regression analysis. The results indicated that hOGG1 Ser326Cys, APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were correlated with the risk of PACG. Furthermore, there were thicker corneas, higher intraocular pressure (IOP) and a shorter axial length in patients carrying the mutant genotypes of hOGG1 Ser326Cys (Ser/Cys + Cys/Cys), APE1 Asp148Glu (Asp/Glu + Glu/Glu) and XRCC1 Arg399Gln (Arg/Gln + Glu/Glu) than those carrying the corresponding wild-type genotypes. According to the logistic regression analysis, Asp148Glu and Arg399Gln polymorphisms, a short axial length and high IOP are major risk factors for PACG. These findings reveal that hOGG1 Ser326Cys, APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms are correlated with the risk and clinicopathological features of PACG in a Chinese Han population.

The Investigation of Polymorphisms in DNA Repair Genes (XRCC1, APE1 and XPD) in Women with Polycystic Ovary Syndrome

Background:PCOS was reported to arise from the interaction of genetic and environmental factors. Some studies reported that women with PCOS have DNA damage and chromosome breakage. Such studies bring to mind the genes that are involved in DNA repairing. At present, several DNA repair genes and, as products of these genes, certain polymorphisms that alter the activity of proteins are known in the literature. The aim of this dissertation is to study the genomic instability that have been reported in PCOS cases along with the relationship between XRCC1 Arg194Trp, XRCC1 Arg399Gln, APE1 Asp148Glu, and XPD Lys751Gln polymorphisms in order to contribute to the pathogenesis of PCOS.Methods:Polymorphisms in DNA repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of PCOS. Therefore, we conducted a study including 114 women with PCOS and 91 controls. These polymorphisms were determined by quantitative real time PCR and melting curve analysis using LightCycler.Results:Comparing the control groups at the end of the study, the results have not shown any statistically significant difference as far as XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XPD Lys751Gln polymorphisms are concerned. However, there were notable differences between the groups in terms of APE1 Asp148Glu polymorphism. Associated with this condition, it has been noted that both mutant allele (Glu) frequency (37.72 % in the study group; 19.23% in the control group, p=0.0001) and homozygous mutant genotype (Glu/Glu) frequency (%12.28 in the study group; %6.60 in the control group, p=0.015) have been higher in the study group.

Association between APE1 Asp148Glu polymorphism and the risk of urinary cancers: a meta-analysis of 18 case–control studies

BackgroundSeveral observational studies suggested that APE1 Asp148Glu was significantly associated with urinary cancers; however, the results of published studies are inconsistent.Materials and methodsThe PubMed and EMBASE were searched for case–control studies regarding the association between Asp148Glu and the risk of urinary cancers with a time limit of September 12, 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between Asp148Glu and the risk of developing prostate cancer, kidney cancer, bladder cancer, as well as all urinary cancers combined.ResultsA total of 18 case–control studies were included in the analysis. Our meta-analysis revealed that the inheritance of at least one APE1 148Glu among Asian men was associated with a 1.26-fold increase in the risk of developing urinary cancers. Meanwhile, APE1 Asp148Glu was significantly associated with the risk of prostate cancer. However, there were no significant relationships between the APE1 SNP (single nucleotide polymorphism) and all urinary cancers combined and bladder cancer and kidney cancer among the men of Caucasian/Asian/African descent or all racial/ethnic groups combined. When stratified by the quality score, no significant association was found in high-quality studies (score ≥7), but a significant increased risk of urinary cancers was observed in lower quality studies (score <7) (dominant model: OR=1.27, 95% CI=1.11–1.45).ConclusionOur meta-analysis suggests that APE1 Asp148Glu was not associated with the risk of urinary cancers but might increase the risk of urinary cancers among Asians. Stratification by cancer type identified a significant association of Asp148Glu with prostate cancer.

XPD, APE1, and MUTYH polymorphisms increase head and neck cancer risk: effect of gene-gene and gene-environment interactions.

In the present study, we investigated the effect of the DNA repair gene polymorphisms XPD Asp312Asn (G>A), APE1 Asp148Glu (T>G), and MUTYH Tyr165Cys (G>A) on the risk for head and neck cancer (HNC) in association with tobacco use in a population of Northeast India. The study subjects comprised of 80 HNC patients and 92 healthy controls. Genotyping was performed using amplification refractory mutation system-PCR (ARMS-PCR) for XPD Asp312Asn (G>A) and PCR using confronting two-pair primers (PCR-CTPP) for APE1 Asp148Glu (T>G) and MUTYH Tyr165Cys (G>A). The XPD Asp/Asn genotype increased the risk for HNC by 2-fold (odds ratio, OR = 2.072; 95 % CI, 1.025-4.190; p < 0.05). Interaction between APE1 Asp/Asp and XPD Asp/Asn as well as MUTYH Tyr/Tyr and XPD Asp/Asn genotypes further increased the risk by 2.9 (OR = 2.97; 95 % CI, 1.16-7.61; p < 0.05) and 2.3 (OR = 2.37; 95 % CI, 1.11-5.10; p < 0.05) folds, respectively. The risk was further increased in heavy smokers with the XPD Asp/Asn genotype and heavy tobacco chewers with XPD Asn/Asn genotype by 7.7-fold (OR = 7.749; 95 % CI, 2.53-23.70; p < 0.05) and 10-fold (OR = 10; 95 % CI, 1.26-79.13; p < 0.05), respectively. We thus conclude that the XPD Asp312Asn and APE1 Asp148Glu polymorphisms increase the risk for HNC in association with smoking and/or tobacco chewing in the population under study.

Association of DNA Repair Gene APE1 Asp148Glu Polymorphism with Breast Cancer Risk.

Objective. The aim of this study was to investigate the role of APE1 Asp148Glu polymorphism in breast cancer progression in Saudi population. Methods. We examined the genetic variations (rs1130409) in the DNA base excision repair gene APE1 at codon 148 (Asp148Glu) and its association with breast cancer risk using genotypic assays and in silico structural as well as functional predictions. In silico structural analysis was performed with Asp148Glu allele and compared with the predicted native protein structure. The wild and mutant 3D structures of APE1 were compared and analyzed using solvent accessibility models for protein stability confirmation. Results. Genotypic analysis of APE1 (rs1130409) showed statistically significant association of Asp148Glu with elevated susceptibility to breast cancer. The in silico analysis results indicated that the nsSNP Asp148Glu may cause changes in the protein structure and is associated with breast cancer risk. Conclusion. Taken together, this is the first report that established that Asp148Glu variant has structural and functional effect on the APE1 and may play an important role in breast cancer progression in Saudi population.

Association between APE1 T1349G polymorphism and prostate cancer risk: evidence from a meta-analysis.

APE1 T1349G polymorphism was considered to be associated with risk of cancer, but studies on the association between APE1 T1349G polymorphism and risk of prostate cancer remained inconclusive. A meta-analysis of published studies was performed to precisely assess the association between APE1 Asp148Glu polymorphism and prostate cancer risk. PubMed, Embase, and Wanfang databases were searched for published case-control studies investigating the association between APE1 T1349G polymorphism and prostate cancer risk. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Overall, seven studies with a total of 3,063 individuals were finally included into the meta-analysis. The heterogeneity analysis did not find obvious heterogeneity among those included studies. Meta-analysis of total seven studies did not find an obvious association between APE1 T1349G polymorphism and prostate cancer risk (G vs T OR (95 % CI) = 1.11 (0.99-1.24); GG vs TT OR (95 % CI) = 1.25 (0.96-1.62); TG vs TT OR (95 % CI) = 1.11 (0.95-1.30); GG/TG vs T OR (95 % CI) = 1.13 (0.97-1.32); GG vs TT/TG OR (95 % CI) = 1.16 (0.91-1.48)). Subgroup analyses by ethnicity showed that APE1 T1349G polymorphism was associated with increased risk of prostate cancer in Caucasians (G vs T OR (95 % CI) = 1.26 (1.02-1.56), P = 0.033; TG vs TT OR (95 % CI) = 1.44 (1.06-1.94), P = 0.019; GG/TG vs T OR (95 % CI) = 1.45 (1.08-1.94), P = 0.013). The meta-analysis suggests that APE1 T1349G polymorphism is associated with increased risk of prostate cancer, especially in Caucasians. More studies are needed to further identify the obvious association above.

Association between OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and breast cancer risk: a meta-analysis.

BackgroundThe base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. OGG1 and APE1 are two important genes in the BER pathway. Many epidemiological studies have evaluated the association between polymorphisms in the two BER genes (OGG1 Ser326Cys and APE1 Asp148Glu) and breast cancer risk. However, the results are inconsistent.MethodsWe searched the electronic databases including PubMed, Embase and Cochrane library for all eligible studies for the period up to February 2014. Data were extracted by two independent authors and pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.ResultsA total of 17 studies including 9,040 cases and 10,042 controls were available for OGG1 Ser326Cys polymorphism and 7 studies containing 2,979 cases and 3,111 controls were included for APE1 Asp148Glu polymorphism. With respect to OGG1 Ser326Cys polymorphism, we did not find a significant association with breast cancer risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and menopausal status, statistical significant increased breast cancer risk was found in Asian populations (Cys/Cys vs. Ser/Ser: OR = 1.157, 95% CI 1.013–1.321, P = 0.011; Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.113, 95% CI 1.009–1.227, P = 0.014) and postmenopausal patients (Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.162, 95% CI 1.003–1.346, P = 0.024). In subgroup analysis according to quality score, source of control, and HWE in controls, no any significant association was detected. With respect to APE1 Asp148Glu polymorphism, no significant association with breast cancer risk was demonstrated in the overall and stratified analyses.ConclusionsThe present meta-analysis suggests that the OGG1 Ser326Cys polymorphism may be a risk factor for breast cancer in Asians and postmenopausal patients. Further large and well-designed studies are needed to confirm this association.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1156934297124915

The association between the APE1 Asp148Glu polymorphism and breast cancer susceptibility: a meta-analysis based on case–control studies

Published data regarding the association between the APE1 Asp148Glu polymorphism and breast cancer susceptibility showed inconclusive results. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, Elsevier, and Springer for relevant articles published before December 10. 2013. The strength of association between APE1 Asp148Glu polymorphism and breast cancer susceptibility was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95% CI) using the software Stata (version 10.0). A total of 7 case-control studies including 3,460 cases and 3,909 controls were included for analysis. Overall, no significant associations were found between the APE1 Asp148Glu polymorphism and breast cancer susceptibility for GG vs TT (OR = 1.00, 95% CI = 0.87-1.14); TG vs TT (OR = 1.06, 95% CI = 0.95-1.18); the dominant model GG + TG vs TT (OR = 1.04, 95% CI = 0.94-1.16) and the recessive model GG vs TG + TT (OR = 0.99, 95% CI = 0.88-1.11). In subgroup analysis, a significant association was found for TG vs TT in Asian subgroup (OR = 1.17, 95% CI = 1.00 ~ 1.36) and in population-based subgroup (OR = 1.18, 95% CI = 1.00 ~ 1.38). This meta-analysis suggested that the APE1 Asp148Glu polymorphism was a risk factor for breast cancer susceptibility among Asian population.

The association of APE1 Asp148Glu gene polymorphisms and lung cancer risk: an updated meta-analysis

Many studies have examined the association between APE1 Asp148Glu (rs3136820) polymorphism gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. PubMed and CNKI databases were searched for case-control studies published up to October 2013. Data were extracted, and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Ultimately, 14 studies, comprising 4,165 lung cancer cases and 5,438 controls were included. Overall, for Glu carriers (Asp/Glu + Glu/Glu) versus wild-type homozygotes (Asp/Asp), the pooled OR was 1.05 (95% CI = 0.96-1.15 P = 0.000 for heterogeneity); for Glu/Glu versus Asp/Asp, the pooled OR was 1.07 (95% CI = 0.95-1.21 P = 0.007 for heterogeneity). In the stratified analysis by ethnicity, the significantly risks were not found among Asians or Caucasians. This updated meta-analysis suggests that the APE1 Asp148Glu polymorphisms are not associated with lung cancer risk among Asians or Caucasians.

The APE1 Asp148Glu polymorphism and colorectal cancer susceptibility: a meta-analysis

Published data regarding the association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility remained controversial. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, and Web of Science with a time limit of August 19, 2013. Summary odds ratios (ORs) with 95% CIs were used to assess the strength of association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility using random-effects model. A total of eight case-control studies including 2,597 cases and 3,063 controls were included for analysis. Overall, no significant associations were found between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility for GG vs TT (OR = 1.00, 95% CI = 0.73-1.36, p = 0.00 for heterogeneity), TG vs TT (OR = 1.17, 95% CI = 0.88-1.55, p = 0.00 for heterogeneity), the dominant model GG + TG vs TT (OR = 1.21, 95% CI = 0.91-1.60, p = 0.00 for heterogeneity) nor the recessive model GG vs TG + TT(OR = 0.95, 95% CI = 0.75-1.20, p = 0.02 for heterogeneity). In subgroup analysis, no significant associations were found in the Asian or Caucasian populations. This meta-analysis suggested that the APE1 Asp148Glu polymorphism was not associated with colorectal cancer susceptibility among Asians or Caucasians.

The Polymorphism Of Base Excision Repair Gene, XRCC1 Arg399Gln Is Associated With The Therapy-Related Myelodysplastic Syndromes (MDS)

BackgroundBase excision repair (BER) is critical for genome maintenance, and is mainly responsible for the correction of small base changes of DNA damage. BER pathway involved many enzymes including OGG1, XRCC1, APE1 and MUTYH. Single nucleotide polymorphisms (SNPs) in DNA repair genes result reduced DNA repair capacity, have been reported to be associated with an increased risk of various cancers including hematologic malignancies. However, it is unclear that these polymorphisms alter the susceptibility and clinical outcome of myelodysplastic syndromes (MDS) patients. The aim of this study is to evaluate the association of polymorphisms in gene encoding four key proteins of DNA BER: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYHGln324His with the susceptibility and clinical features of MDS. MethodsOur study included 113 MDS patients [median 68.3 years, range 17.1-86.5 years; male/female 76/37; RCUD (n=37), RARS (n=6), RCMD (n=21), MDS-u (n=11), RAEB-1(n=14), RAEB-2 (n=11), others (n=13)] and 192-health control group. Twenty four patients with MDS had the history of cancer. Genetic polymorphisms in BER pathway genes were examined using PCR and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between patients group and control group by using χ2-test. All patients and healthy controls received written information about the study. This study was approved by the International Research Board of Gunma University Hospital. ResultsThere was no statistically significant difference in the allele and genotype frequencies of the OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the MDS patients and the control group. In the analysis of clinical characteristics, XRCC1 non Arg/Arg genotype (low DNA repair type) was significantly associated with lower Hb level (8.64±2.29g/dL vs. 9.96±2.08 g/dL, p<0.005) and higher frequency of the complex karyotype (14.9% vs. 2.8%, p=0.05). Furthermore, XRCC1 non Arg/Arg genotype was associated with therapy- related MDS (OR 3.15, 95% CI 1.24-7.98, p=0.02) and especially the past history of radiotherapy (14.3% vs. 0%, p<0.005). In contrast, the polymorphisms in OGG1 Ser326Cys, APE1 Asp148Glu, and MUTYH Gln324His were not involved in the clinical features of MDS. ConclusionThe low DNA repair polymorphism, XRCC1 Arg399Gln is associated with the clinical features of MDS, including therapy- related MDS. Further investigation of BER polymorphisms will provide the understanding of pathogenesis of therapy- related MDS in a larger sample size analysis. Disclosures:No relevant conflicts of interest to declare.

Genetic variants of the APE1 gene and the risk of vitiligo in a Chinese population: A genotype–phenotype correlation study

Vitiligo is an acquired depigmentation disorder, and reactive oxygen species play an important role in melanocyte damage. Base excision repair is the major pathway responsible for removing reactive oxygen species-induced DNA damage, in which APE1, ADPRT, and XRCC1 play key roles. To investigate the association between genetic variations of these genes and the risk of vitiligo in Chinese populations, we genotyped APE1-Asp148Glu, ADPRT-Val762Ala, and XRCC1-Arg399Gln polymorphisms and measured serum 8-OHdG levels in a hospital-based case–control study. We found that a significantly increased risk of vitiligo was associated with the APE1 Asp/Glu (adjusted odds ratio (OR) 1.24; 95% confidence interval (CI) 1.02–1.52) and Glu/Glu genotypes (adjusted OR 1.48; 95% CI 1.13–1.93), compared with the APE1 Asp/Asp genotype, whereas no vitiligo risk was associated with the genotypes ADPRT-Val762Ala and XRCC1-Arg399Gln. Furthermore, serum 8-OHdG levels were elevated in the APE1-148Glu allele carriers (Asp/Glu+Glu/Glu), in an allele dose-response manner, with the risk of vitiligo (Ptrend<0.05). In addition, we found that the APE1-148Glu variant increased the 8-OHdG levels of cultured human melanocytes treated with H2O2, without any impact on the endonuclease activity. These data suggest that the APE1-Asp148Glu polymorphism aggravates oxidative stress in human melanocytes and contributes to genetic predisposition to vitiligo in Chinese people.

Lack of an Association between Two BER Gene Polymorphisms and Breast Cancer Risk: A Meta-Analysis

BackgroundThe base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. ADPRT and APE1 are two important genes in the BER pathway. Several studies have evaluated the association between polymorphisms in the two BER genes (ADPRT Val762Ala and APE1 Asp148Glu) and breast cancer risk. However, the results are inconsistent.Methodology/Principal FindingsIn this study, we conducted a meta-analysis to derive a more precise estimation. A total of 8 studies were included in the meta-analysis (6 studies with 2,521 cases and 2,652 controls for ADPRT Val762Ala polymorphism and 5 studies with 2,539 cases and 2,572 controls for APE1 Asp148Glu polymorphism). For ADPRT Val762Ala polymorphism, no obvious associations were found for all genetic models (Val/Ala vs. Val/Val: OR = 0.960, 95% CI = 0.845–1.090; Ala/Ala vs. Val/Val: OR = 0.897, 95% CI = 0.683–1.178; dominant model: OR = 0.953, 95% CI = 0.843–1.077; and recessive model: OR = 1.084, 95% CI = 0.838–1.403). For APE1 Asp148Glu polymorphism, also no obvious associations were found for all genetic models (Asp/Glu vs. Asp/Asp: OR = 0.947, 95% CI = 0.829–1.082; Glu/Glu vs. Asp/Asp: OR = 0.958, 95% CI = 0.813–1.129; dominant model: OR = 0.946, 95% CI = 0.835–1.072; and recessive model: OR = 1.004, 95% CI = 0.873–1.155). In the subgroup analysis by ethnicity or study design, still no obvious associations were found.Conclusions/SignificanceThis meta-analysis indicates that ADPRT Val762Ala and APE1 Asp148Glu polymorphisms are not associated with increased breast cancer risk.

The Polymorphisms of Base Excision Repair Genes Influence the Prognosis of Multiple Myeloma

AbstractAbstract 3981 Background:The DNA in human cells is oxidatively damaged by various endogenous biochemical processes or exogenous stimuli. Base excision repair (BER) systems have important role for repairing oxidative DNA damage, and known to influence the carcinogenesis and the response to anti-cancer treatments. Although previous studies have shown that defective DNA repair is associated with an increased risk of hematologic malignancies including leukemia and lymphoma, it is unclear these polymorphisms alter the susceptibility and clinical outcome of multiple myeloma (MM) patients. The aim of this study was to evaluate the impact of polymorphisms in genes encoding four main proteins of BER system: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His on the risk and survival of MM. Methods:We examined 93 patients [age range, 35–83 years; male/female44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); Intenational staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory (n=3), Bence Jones (n=18)] with MM and 192 healthy controls. Genomic DNA was isolated from peripheral blood using the DNA extraction kit. Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Allele and genotype frequencies were calculated by direct counting. Genotype and allele frequencies were compared between patients group and control group by using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). Difference between the survival curves by genotypes was compared using the generalized Wilcoxon test. For the multivariate survival analyses, cox proportional hazard models were used to define the prognostic factors for OS. Probability values <0.05 were considered statistically significant. All patients and healthy controls received written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results:The frequencies of genotypes of BER gene polymorphism in patients with MM were as follows: Ser/Ser 35.9%, Ser/Cys 34.8%, and Cys/Cys 29.3% for OGG1; Gln/Gln 22.6%, Gln/His 49.5%, and His/His 28% for MUTYH; Arg/Arg 57%, Arg/Gln 38.7% and Gln/Gln 4.3% for XRCC1; Asp/Asp 35.5%, Asp/Glu 41.9%, and Glu/Glu 22.6% for APE1. These results showed the OGG1 Cys/Cys genotype (low DNA repair type) compared with OGG1 non-Cys/Cys genotype increases the risk of MM (OR 1.86, 95% CI 1.04–3.31, p<0.05). Furthermore, the Ser/Cys genotype compared with OGG1 non-Ser/Cys genotype strongly reduces the risk of MM (OR 0.39; 95% CI 0.24–0.06, p<0.0005). In contrast, there was no statistically significant difference about the risk of MM in the allele and genotype frequencies of the XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the control group and the patients with MM. When comparing OS according to APE1 Asp148Glu polymorphism, the group with APE1 Glu/Glu (low DNA repair type) showed inferior OS (median OS 3.07 years vs.5.63 years, p=0.02). In a multivariate analysis using stepwise selection, APE Glu/Glu (low DNA repair type) (p=0.02), MUTYH His/His (low DNA repair type) (p=0.0001), ISS 3 (p=0.003), and Hb<10 g/dl (p=0.03) were independent prognostic factors significantly associated with shorter survival. Conclusions:According to our data, BER gene polymorphisms may affect the carcinogenesis and prognosis of MM. It is suspected that low BER activity gave rise to high DNA damage, and induced malignant transformation of plasma cell and progression to aggressive myeloma. The BER gene polymorphisms may be one of useful prognostic markers of MM and require further verification as predictive biomarkers in a larger study population. Disclosures:No relevant conflicts of interest to declare.

Association of DNA repair gene polymorphism with chromosomal aberrations frequency in human lymphocytes

Analysis of the association between several DNA repair gene polymorphisms and the level of chromosomal aberrations (CAs) in lymphocytes of two groups of adolescents was carried out: in a group of 256 donors exposed to indoor radon and a control group of 94 donors. In a group of children with living conditions exposing them to high doses of radon (>200 Bq/m3), the level of CAs was significantly higher among carriers of genotypes hOGG1 Cys/Cys, hOGG1 Ser/Cys, ADPRT Ala/Ala, and ADPRT Val/Ala. No significant association between the level of CA and XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, and APE1 Asp148Glu polymorphisms was found.

Genetic Polymorphisms in DNA Repair Genes OGG1, APE1, XRCC1, and XPD and the Risk of Age-Related Cataract

To analyze the association of the polymorphisms in 8-oxoguanine glycosylase-1 (OGG1), X-ray repair cross-complementing-1 (XRCC1), and AP endonuclease-1 (APE1) genes in the base excision repair pathway and xeroderma pigmentosum complementation group D (XPD) in the nucleotide excision repair pathway with the risk of cataract in a Chinese population. Case-control study. Subjects with cataract (n = 415) or no cataract (n = 386) in the Age Related Eye Disease Ancillary Study. The study included 415 cataract patients and 386 controls. Genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism method. Differences in the frequencies were estimated by the chi-square test, and risk was estimated by using unconditional logistic regression after adjusting for age and gender. Association of single nucleotide polymorphisms in OGG1-Ser326Cys with the development of age-related cataract. The OGG1 Cys/Cys genotype frequency was significantly higher in cataract patients (P = 0.014; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.171-3.624). The OGG1 Ser/Ser genotype (P = 0.003; OR, 0.647; 95% CI, 0.487-0.860) seems to have a protective role against cataract, and the Cys allele (P<0.001; OR, 1.517; 95% CI, 1.204-1.911) seems to have a deleterious role in the development of cataract. The genotype frequency of the Ser/Ser of OGG1-Ser326Cys was significantly different in the cortical and mixed-type cataract group (P = 0.014; OR, 0.591; 95% CI, 0.391-0.893; and P = 0.035; OR, 0.639; 95% CI, 0.425-0.960; respectively), and the Cys/Cys genotype of OGG1-Ser326Cys was significantly different in the mixed-type cataract group (P = 0.012; OR, 2.610; 95% CI, 1.284-5.306) compared with that of healthy controls. In XRCC1-Arg399Gln, APE1-Asp148Glu, and XPD-Lys751Gln polymorphisms, there were no significant differences in frequencies of the variant homozygous in patients compared with controls. Results suggest that the Cys/Cys genotype of the OGG1-Ser326Cys polymorphism may be associated with increased risk of age-related cataract. However, in XRCC1-Arg399Gln, APE1-Asp148Glu, and XPD-Lys751Gln polymorphisms, there were no significant differences in frequencies of the variant homozygous in patients compared with controls.