OGG1 Ser326Cys Research Articles

The Human 8-oxoG DNA Glycosylase 1 (OGG1) Ser326Cys Polymorphism in Infertile Men.

8-hydroxy-2'-deoxyguanosine (8-OHdG) is a form of oxidative DNA damage caused by oxidative stress (OS), which is considered a major factor in male infertility. The cellular defense system against 8-OHdG involves base excision repair (BER) with the enzyme 8-Oxoguanine DNA glycosylase 1 (OGG1). However, studies on the single-nucleotide polymorphism (SNP) OGG1 Ser326Cys have demonstrated that the Cys326Cys genotype could be the cause of an increment in oxidative DNA damage. In this study, the OGG1 Ser326Cys polymorphism and its effect on DNA oxidation were evaluated in 118 infertile men. Polymorphic screening was performed using TaqMan allelic discrimination assays, and oxidative DNA damage was evaluated through the quantification of 8-OHdG and total antioxidant capacity (TAC); in addition, electrical bioimpedance spectroscopy (EBiS) measurements were used as a reference for different electrical properties associated with 8-OHdG concentrations. The detected Cys (G) allele frequency (0.4) was higher compared to the allele frequency reported in the "Allele Frequency Aggregator" (ALFA) and "Haplotype Map" (HapMap) projects for American populations (0.21-0.29), suggesting that the Cys (G) allele carrier could be a factor associated with American infertile populations. The values of 8-OHdG were twofold higher in carriers of the Cys326Cys (GG) genotype than the other genotypes and, in concordance, the TAC levels were threefold lower in Cys326Cys (GG) genotype carriers compared to the other genotypes. Moreover, the EBiS magnitude exhibited potential for the detection of different oxidative damage in DNA samples between genotypes. The Cys326Cys (GG) genotype is associated with oxidative DNA damage that could contribute to male infertility.

Investigation of the association between polymorphisms in DNA repair enzymes and STEMI

STEMI (ST-elevation myocardial infarction), a condition in which DNA damage likely contributes to its pathogenesis, is among the most severe manifestations of coronary artery disease. There are very few publications in this field in the literature. In our study, we examined the association between four polymorphisms in repair enzymes (LIG4 Thr9Ile, XRCC6 promoter C-57G, XPA -4A/G, OGG1 Ser326Cys) involved in three distinct DNA repair mechanisms [NHEJ (non-homologous end joining)], NER (nucleotide excision repair), and BER (base excision repair), and their impact on the risk of STEMI. This study involved 185 patients diagnosed with STEMI and included 155 healthy controls. The genotyping of SNPs was conducted through the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) method for the following variants: XRCC6 (rs2267437), XPA (rs1800975), LIG4 (rs1805388), and OGG1 (rs1052133). No significant differences were observed in the genotype distributions of the XRCC6 and OGG1 variations between the control and patient groups. On the other hand, our findings indicate that individuals carrying the mutant G allele for XPA polymorphism and the mutant T allele for LIG4 polymorphism are susceptible to STEMI. Our findings demonstrate the significance of NHEJ and NER DNA repair processes in the pathogenesis of STEMI, as evidenced by the observed relationship between LIG4 and XPA polymorphisms.

The OGG1 and TP53 polymorphisms and susceptibility to breast cancer in Northwestern Iran

The hallmarks of malignant illnesses include defective DNA repair capability and disruption of genomic integrity brought on by the accumulation of different types of DNA damage. In the case of breast cancer, previous research has suggested that specific SNPs within genes involved in DNA repair and tumor suppression pathways, such as OGG1 and TP53, may modulate an individual's susceptibility to the disease.TP53 and OGG1 play a significant role in genome integrity and DNA repair. The genetic variation in TP53 and OGG1 reduces the repair function and increases cancer risk. The present study aimed to evaluate the single nucleotide polymorphisms of these two genes to show the combined effect of TP53 and OGG1 genotypes in breast cancer. The present case-control study was carried out by collecting blood samples from 166 patients with breast cancer and 166 individuals without a personal history of breast cancer. Tetra-ARMS and AS-PCR were used to ascertain the genotypes. The online Javastat statistics package, MDR, and IBM SPSS Statistics 26 were used to analyze the data. In silico analysis was performed to evaluate the effects of OGG1 and TP53. A strong synergistic interaction between TP53 and OGG1, moderate synergistic interaction between OGG1 and age, and correlation between TP53 and age was indicated, suggesting a novel interaction between TP53 and OGG1. Moreover, the recessive model of the OGG1 Ser326Cys polymorphism (P = 0.039) had a protective effect against breast tumors. We found no significant relationship between TP53 Arg72Pro and susceptibility to breast cancer. In this study, the results suggested the OGG1- Ser326Cys GG genotype as a protective factor against the risk of breast cancer in a representative sample of Iranian-Azeri women. Also, using the MDR method, we discovered a gene-gene association between TP53 and OGG1.

The Long-Term Impact of Ionizing Radiation on DNA Damage in Patients Undergoing Multiple Cardiac Catheterizations.

Ionizing radiation (IR) exposures have increased exponentially in recent years due to the rise in diagnostic and therapeutic interventions. A number of small-scale studies investigated the long-term effect of IR on health workers or immediate effects of IR on patients undergoing catheterization procedures; however, the long-term impact of multiple cardiac catheterizations on DNA damage on a patient population is not known. In this study, the effects of IR on DNA damage, based on micronuclei (MN) frequency and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as markers in peripheral lymphocytes, were evaluated in patients who previously underwent multiple cardiac catheterization procedures. Moreover, genetic polymorphisms in genes PARP1 Val762Ala, OGG1 Ser326Cys, and APE1 Asn148Glu as a measure of sensitivity to radiation exposure were also investigated in the same patient population. The patients who underwent ≥ 3 cardiac catheterization procedures revealed higher DNA injury in comparison to the patients who underwent ≤ 2 procedures, documented with the presence of higher level of MN frequency (6.4 ± 4.8 vs. 9.1 ± 4.3, p = 0.002) and elevated serum 8-OHdG levels (33.7 ± 3.8ng/mL vs. 17.4 ± 1.9ng/mL, p = 0.001). Besides, OGG1 Ser326Cys and APE1 Asn148Glu heterozygous and homozygous polymorphic types, which are related with DNA repair mechanisms, were significantly associated with MN frequency levels (p = 0.006 for heterozygous and p = 0.001 for homozygous with respect to OGG1 Ser326Cys, p = 0.007 for heterozygous and p = 0.001 for homozygous with respect to APE1 Asn148Glu). There was no significant difference in terms of PARP1 Val762Ala gene polymorphism between two groups.

The High Lead Level Role in the DNA Repair RAD 18 and OGG1 Gene Polymorphism in Gasoline Station Workers

The DNA repair enzymes–heavy metal interaction is an interesting project that can help elucidate several diseases. The current study aims to assess the lead effect in the two DNA repair genes RAD-18 Arg302Gln (rs373572) and OGG1 Ser326Cys in Gasoline station workers. The output showed that work types were Gasoline supply worker with a high percentage (73.52%) than other groups (11.76% and 14.7%) for a maintenance worker and station employee, respectively, significant lead (p 0.010) increasing in station worker than the control group, and significant lead changes among work types groups (p 0.000), the station employee has a low level of lead than other groups, while the Gasoline supply worker has a higher level than other groups, the RAD 18 gene showed two polymorphisms Gln/Gln and Gln/Arg, and OGG1 showed two haplotypes, single and double haplotypes, non-significant association although of high frequent of Glu/Arg in the gasoline supply worker, and significant association of allele frequency, significant association with station worker that have two types of haplotypes (single and double haplotypes) while lack of tri-haplotypes which prepared in higher percentage in control group. The lead level according to RAD 18 genotyping show non-significant (p 0.454) elevation in Gln/Arg genotyping, and according to OGG 1 haplotype lead level was non-significant, changed (p 0.481) between single and double haplotypes. From these outputs, it can be concluded that the lead level is a significant elevation in gasoline station worker and it did not affect RA18 and OGG 1 genotyping, the RAD18 did not associate with workers while OGG strongly associated with them.

DNA Repair Gene OGG1 Ser326Cys Polymorphism and DNA Damage in Patients with Type 2 Diabetes

8-hydroxydeoxyguanosine (8-OHdG) is the most frequent oxidative DNA damage. 8-oxo-deoxyguanosine DNA glycosylase 1 (OGG1) is involved in the repair of 8-OHdG. Many studies indicated that DNA repair is decreased in type 2 diabetes (T2DM). Single nucleotide polymorphisms in DNA repair genes may be linked to a decrease in DNA repair activity. The main objective of this study was to see how the OGG1 Ser326Cys gene polymorphism affected OGG1 expression and urinary excretion of 8-OHdG in T2DM patients. OGG1 expression and OGG1 genotyping in lymphocytes were detected by immunocytochemical staining and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism assay, respectively. Urinary 8-OHdG levels were measured by using ELISA kit in patients with T2DM. Compared with control cases, patients with T2DM had lower OGG1 immunopositivity and higher urinary 8-OHdG levels. No significant difference was found in OGG1 immunopositivity or urinary 8-OHdG levels between subjects with different OGG1 genotypes in both groups. In conclusion, The OGG1 Ser326Cys gene polymorphism has no effect on neither OGG1 expression nor urinary 8-OHdG levels. Increased urinary 8-OHdG levels despite low OGG1 immunopositivity may be derived from the action of other DNA repair enzymes.

Association of base excision repair pathway genes OGG1, XRCC1 and MUTYH polymorphisms and the level of 8-oxo-guanine with increased risk of colorectal cancer occurrence.

Reduced efficiency of DNA repair systems has long been a suspected factor in increasing the risk of cancer. In this work authors investigate influence of selected polymorphisms of DNA repair genes (XRCC1, OGG1 and MUTYH) and level of oxidative damage (measured as level of 8-oxo-guanine, 8-oG) on modulation of the risk of colorectal cancer. In group of 324 patients with colorectal cancer the occurrence of polymorphic variants in Ser326Cys of OGG1, Arg399Gln of XRCC1 and Gln324His of MUTYH were studied with TaqMan technique. In addition level of 8-oG in isolated DNA was determined. Studied polymorphisms of OGG1, XRCC1 and MUTYH genes influence the risk of CRC: OGG1 Ser326Cys (OR = 1.259, 95% CI: 1.058-1.499, p = 0.007), XRCC1 Arg399Gln (OR = 2.481, 95% CI: 1.745-3.529, p < 0.0001) and MUTYH Gln324His (OR = 1.421, 95% CI: 1.017-1.984, p = 0.039) increase the risk. At the same time, studies examined level of 8-oG for each of the genotypes in both the patient and control group, and have shown that OGG1 Ser326Cys and XRCC1 Arg399Gln are associated with elevated 8-oG level, while MUTYH Gln324His is not, suggesting, that in case of OGG1 Ser326Cys and XRCC1 Arg399Gln CRC risk modulation is connected to mechanisms associated with 8-oG levels. This work shows that patients with CRC not only have an increased level of 8-oG and that the studied polymorphisms modulate risk of cancer, but also indicate a relationship between these 2 phenomena, which may contribute to a better understanding of the mechanism of neoplastic process in case of reduced effectiveness of DNA repair mechanisms. Int J Occup Med Environ Health. 2022;35(5):625-33.

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay and its relationship with genetic polymorphisms in welders

Fumes generated in the welding process are composed of micrometric and nanometric particles that form when metal fumes condense. The International Agency for Research on Cancer established that many compounds derived from the welding process are carcinogenic to humans. Still, there are few studies related to the role of genetic polymorphisms. This work aimed to analyze the influence of OGG1 Ser326Cys, XRCC1 Arg280His, XRCC1 Arg194Thr, XRCC1 Arg399Gln, XRCC3 Thr241Met, GSTM1, and GSTT1 gene polymorphisms on DNA damage of 98 subjects occupationally exposed to welding fumes and 100 non exposed individuals. The results showed that individuals exposed to welding fumes with XRCC3 Thr241Thr, XRCC3 Thr241Met, and GSTM1 null genotypes demonstrated a significantly higher micronucleus frequency in lymphocytes. In contrast, individuals with XRCC1 Arg399Gln and XRCC1 Gln399Gln genotypes had significant levels of NPBs. OGG1 326 Ser/Cys, OGG1 326 Cys/Cys, XRCC1 194Arg/Thr, XRCC1 194Thr/Thr, and GSTT1 null genotypes exhibited significantly higher apoptotic values. Also, XRCC1 194Arg/Trp, XRCC1 194Thr/Thr, and GSTM1 null genotype carriers had higher necrotic levels compared to XRCC1 194Arg/Arg and GSTM1 nonnull carriers. Compositional analysis revealed the presence of iron, manganese, silicon as well as particles smaller than 2 μm that adhere to each other and form agglomerates. These results may be associated with a mixture of components, such as nitrogen dioxide, carbon monoxide, and metallic fumes, leading to significant DNA damage and cell death processes. These findings demonstrated the importance of the association between individual susceptibility and DNA damage levels due to occupational exposure to welding fumes; and constitute one of the first studies carried out in exposed workers from Colombia.

The Role and Therapeutic Target of Base Excision Repair Genes in Multiple Myeloma (MM)

Background: Dysregulated DNA repair genes play a pathological role in diverse forms of malignancies, including multiple myeloma (MM). High expression of some DNA repair enzymes has been reported in various tumors and associated with their progression and drug resistance. Here, we investigated the association between MM and base excision repair (BER) system, which is known as a DNA repair pathway for the processing of small base lesions derived from oxidation and alkylation damages. To elucidate the roles of BER in the pathogenesis of MM, we investigated the distribution of functional polymorphisms of BER, the expression level of BER genes, and the effectiveness of BER inhibitors and knockdown BER genes for MM cell lines.Material and methods: Genotyping of OGG1 Ser326Cys, MUTYH Gln324His, APE1 Asp148Glu, XRCC1 Arg399Gln, and PARP1 Val762Ala in 146 MM patients and 202 race-matched healthy controls was determined by using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Mononuclear cells were separated from bone marrow aspirates and CD138+ cells were collected using EasySep. The mRNA expression of BER genes in MM cell lines (KMM1, KMS12PE, KMSE12BM, KMS11, RPMI8226, and OPM2), primary MM cells, and normal plasma cells was assessed by real-time PCR method. The protein level of BER genes was assessed by western blot analysis. BER inhibitors, including APE1 inhibitor and PARP inhibitor were used. Inducible knockdown system was used for suppressed OGG1 expression. Genotype and allele frequencies were compared between the study groups using Χ2-test. Probability values <0.05 were considered statistically significant. This study was approved by the Institutional Review Board of Gunma University Hospital.Results: The PARP1 Val762Ala single nucleotide polymorphism, which is reported to increase cancer risk, was associated with susceptibility to MM. In the patient group, the Val/Val genotype frequency was lower (32.9% compared with 43.6%, P = 0.044) and the Val/Ala genotype frequency was higher (56.8% compared with 43.1%, P = 0.011) than those in the control groups. In contrast to PARP1 polymorphism, the distributions of other BER polymorphisms, including OGG1 Ser326Cys, MUTYH Gln324His, APE1 Asp148Glu, and XRCC1 Arg399Gln, showed no significant difference between MM patients and control groups. Next, we examined the association between the polymorphisms and the clinical characteristics of MM patients. No significant difference was observed in the allele frequency as well as in sex, age, other clinical settings, and overall survival. The BER genes, such as OGG1, APE1, and PARP1, were detected in all MM cell lines. Protein expression of OGG1, APE1, and PARP1 correlated with mRNA expression in MM cell lines. The mRNA levels of OGG1, APE1, and PARP1 of malignant plasma cells of MM patients were significantly higher than those of normal plasma cells (p < 0.05). The mRNA levels of OGG1, APE1, and PARP1 genesof plasma cells of newly diagnosed MM patients were significantly higher than those of refractory or relapsed MM patients. We exposed MM cell lines to increasing concentrations of APE-1 inhibitor, methoxamine, and PARP1-selective inhibitor, BYK204165, which demonstrated potent and selective growth inhibition in vitro. To determine the role of OGG1 gene in MM growth and survival, we suppressed its expression using an inducible knockdown system and observed significant inhibition of MM cell lines (KMS11 and KMM1) proliferation.Conclusion: The PARP1 Val762Ala polymorphism may be associated with the susceptibility to MM. High expression of BER genes such as OGG1, APE1, and PARP1 was detected in malignant plasma cells, and the inhibition of these BER genes reduced MM cell growth. According to these results, inhibition of BER genes may be a potential therapeutic target of MM. DisclosuresMurakami:Sanofi: Honoraria; Fujimoto: Honoraria; BMS: Honoraria; Ono: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Single Nucleotide Polymorphisms (SNPs) of OGG1 (Ser326Cys) and APE1 (Asp148Glu; –141T/G) Genes and Breast Cancer Risk in Filipino Women

Base excision repair (BER) pathway involves repair of damaged DNA caused by spontaneous decay of DNA, reactive oxygen species, and ionizing radiation. Polymorphisms of genes involved in the pathway have been reported to be associated with cancer risk. In this study, the association of BER gene polymorphisms with breast cancer risk in Filipino women was assessed. The polymorphisms studied included X-ray repair cross-complementing group 1 (XRCC1, Arg399Gln), 8-oxoguanine DNA glycosylase (OGG1, Ser326Cys), and apurinic/apyrimidinic endonuclease 1 (APE1, Asp148Glu; –141T/G). A total of 186 participants (93 breast cancer cases and 93 breast cancer-free control) were recruited for the study. The genotyping of samples was performed using polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The association of polymorphisms of BER genes with breast cancer risk and gene-environment interaction was determined using the unconditional logistic regression model. Distributions of OGG1 and APE1 genotypes were in Hardy-Weinberg equilibrium (HWE); however, XRCC1 genotype distribution deviated from HWE and was not further analyzed. The analysis showed that OGG1 Ser326Cys, APE1 Asp148Glu, and APE1 –141T/G had no significant association with breast cancer risk. Also, there is no significant interaction between the three BER gene variants and family history of cancer. Lastly, no significant increased risk was observed when the combined effects of risk alleles of the three BER gene variants were determined. In conclusion, the study suggests that OGG1 Ser326Cys, APE1 Asp148Glu, and APE1 –141T/G are not good indicators of breast cancer risk in Filipino women.

Genetic polymorphisms in XRCC1, OGG1, and XRCC3 DNA repair genes and DNA damage in radiotherapy workers.

DNA damage may develop at any dose of ionizing radiation. DNA damage activates pathways that regulate cell growth and division or coordinate its replication and repair. The repair pathways, base excision repair (BER) and single-strand break repair (SSBR), can repair such damages efficiently and maintain genome integrity. Loss of this repair process or alteration of its control will be associated with serious outcomes for cells and individuals. This study aimed to determine the relationship between XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), OGG1 (Ser326Cys), and XRCC3 (Thr241Met) SNPs and DNA damage and to identify high-risk individuals with reduced DNA repair capacity. This case-control study was conducted on 80 subjects; 50 subjects working in Clinical Oncology and Nuclear Medicine Department in Assiut University Hospital along with 30 controls. A total of 1mL blood samples were collected for Single-Cell Gel Electrophoresis Technique (Comet Assay) for detection of DNA damage in those subjects. A total of 3mL fresh blood samples were collected and analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based technique. DNA damage detected by comet test was significantly high in IR-exposed workers than control. Statistically high significant difference was found in exposed subjects versus control subjects regarding the frequencies of the variant alleles of hOGG1326, XRCC1280 & 399, and XRCC3241. The level of DNA damage was not affected by OGG1326 SNPs when comparing subjects of wild genotype with those of (pooled) variants either in the exposed staff or in the control group while XRCC1280, 399 and XRCC3241 variant alleles had an influence on the studied DNA damage biomarker. Moreover, genotyping distribution pattern was highly variable in relation to gender. The present study indicated a relationship between DNA damage detected by comet test and single nucleotide polymorphisms in genes coding for DNA certain repair enzymes. Individuals occupationally exposed to low doses of ionizing radiation could be at great risk and more susceptible to the increased DNA damage if they have inherited genetic polymorphism.

The correlation of combined OGG1, CYP1A1 and GSTP1 gene variants and risk of lung cancer of male Iraqi waterpipe tobacco smokers.

Genetic polymorphisms of genes whose products are responsible for activities, such as xenobiotic metabolism, mutagen detoxification and DNA-repair, have been predicted to be associated with the risk of developing lung cancer (LC). The association of LC with tobacco smoking has been extensively investigated, but no studies have focused on the Arab ethnicity. Previously, we examined the association between genetic polymorphisms among Phase I and Phase II metabolism genes and the risk of LC. Here, we extend the data by examining the correlation of OGG1 Ser326Cys combined with CYP1A1 (Ile462Val and MspI) and GSTP1 (Ile105Val and Ala103Val) polymorphisms with the risk of LC. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing were carried out for genotyping the OGG1 polymorphisms of 123 LC patients and 129 controls. No significant differences in the frequencies of the OGG1 mutant allele between patients and controls were found. The distributions of heterozygous Ser/Cys or Cys/Cys genotypes of OGG1 were not associated with the risk of LC either according to the histological types of LC or based on waterpipe tobacco (WP) smoking status. In contrast, the combined effect of OGG1 variants with CYP1A1 and GSTP1 variants revealed a significant correlation with the OGG1 Ser326Cys-CYP1A1 MspI variants pairing. This association was significant (p = 0.001) in individuals who carried homozygous or heterozygous variant type genotypes of both genes in a reference with carriers of both wild-type genotypes (wt/wt - wt/wt). The odds ratios were 2.99 (95% CI 1.67-5.36), 2.68 (95% CI 1.08-6.62), and 2.80 (95% CI 1.18-6.69) for those who carried (wt/wt - wt/vt + vt/vt), (wt/vt + vt/vt - wt/wt), and (wt/vt + vt/vt - wt/vt + vt/vt), respectively. The study suggests a limited correlation is present between carrying OGG1 Ser326Cys polymorphism and the risk of developing LC in Arab populations.

Comprehensive analysis of the correlation between base-excision repair gene SNPs and esophageal squamous cell carcinoma risk in a Chinese Han population.

This study sought to assess the relationship between single nucleotide polymorphisms (SNPs) affecting DNA base-excision repair (BER) genes and esophageal squamous cell carcinoma (ESCC) risk in a Han Chinese population. Genes screened for such SNPs included 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 protein (XRCC1). Blood samples that had been collected in a prospective manner were used for DNA extraction, with all DNA samples then being subjected to PCR-restriction fragment length polymorphism genotyping for BER gene SNPs, including APE1 Asp148Glu and -141T/G, OGG1 Ser326Cys, and XRCC1 Arg399Gln. The relationship between these SNPs and ESCC risk was then assessed, with the comparability of the case and control groups being enhanced via propensity score matching (PSM). This study initially included 642 healthy controls and 321 ESCC patients, with PSM optimization leading to a final analyzed total of 311 matched subjects per group (311 total). Factors associated with elevated ESCC risk in this analysis included advanced age, being male and smoking. We further identified that the XRCC1 399 Gln/Gln genotype was associated with a significant reduction in ESCC risk prior to propensity matching (odds ratio=0.48; 95% CI: 0.23-1.00; P<0.05), although this did not remain true following matching. For the remaining analyzed SNPs, no significant associations between genotype and ESCC risk were detected prior to or following propensity matching. A multivariate analysis incorporating patient age, sex, smoking status and drinking status failed to detect any relationship between the four tested genotypes and ESCC risk. In conclusion, being male, a smoker or of advanced age was associated with an elevated ESCC risk. However, we did not detect any significant relationship between ESCC risk and BER polymorphisms in XRCC1, OGG1, APE1 or the APE1 promoter region in a Han Chinese population.

DNA repair and metabolic gene polymorphisms affect genetic damage due to diesel engine exhaust exposure.

Diesel engine exhaust (DEE) is a complex mixture of toxic gases, halogenated aromatic hydrocarbons, alkyl polycyclic aromatic hydrocarbons, polycyclic aromatic hydrocarbons, benzene derivatives, metals and diesel exhaust particles (DEPs) generated from the incomplete combustion of diesel fuel. Many of the compounds in this mixture can cause oxidative damage to DNA and are considered carcinogenic for humans. Further, chronic DEE exposure increases risks of cardiovascular and pulmonary diseases. Despite these pervasive health risks, there is limited and inconsistent information regarding genetic factors conferring susceptibility or resistance to DEE genotoxicity. The present study evaluated the effects of polymorphisms in two base excision repair (BER) genes (OGG1 Ser326Cys and XRCC1 Arg280His), one homologous recombination (HRR) gene (XRCC3 Thr241Met) and two xenobiotic metabolism genes (GSTM1 and GSTT1) on the genotoxicity profiles among 123 mechanics exposed to workplace DEE. Polymorphisms were determined by PCR-RFLP. In comet assay, individuals with the GSTT1 null genotype demonstrated significantly greater % tail DNA in lymphocytes than those with non-null genotype. In contrast, these null individuals exhibited significantly lower frequencies of binucleated (BN) cells and nuclear buds (NBUDs) in buccal cells than non-null individuals. Heterozygous hOGG1 326 individuals (hOGG1 326 Ser/Cys) exhibited higher buccal cell NBUD frequency than hOGG1 326 Ser/Ser individuals. Individuals carrying the XRCC3 241 Met/Met polymorphism also showed significantly higher buccal cell NBUD frequencies than those carrying the XRCC3 241 Thr/Thr polymorphism. We found a high flow of particulate matter with a diameter of < 2.5μm (PM2.5) in the workplace. The most abundant metals in DEPs were iron, copper, silicon and manganese as detected by transmission electron microscopy-energy-dispersive X-ray spectroscopy (TEM-EDX). Scanning electron microscopy (SEM-EDS) revealed particles with diameters smaller than PM2.5, including nanoparticles forming aggregates and agglomerates. Our results demonstrate the genotoxic effects of DEE and the critical influence of genetic susceptibility conferred by DNA repair and metabolic gene polymorphisms that shed light into the understanding of underlying mechanisms.

MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia

BackgroundDespite conflicting results, considerable evidence suggests the association between single nucleotide polymorphisms in MTHFR, XRCC1 and OGG1 genes and, risk of developing breast cancer. Here a case-control study is reported, including 135 breat cancer patients and 112 healthy women, all representative of Northern Sardinian population.MethodsPolymerase chain reaction/restriction fragment length polymorphism method was used to determine the genotypes of five polymorphisms: MTHFR C677T (rs1801133) and A1298C (rs1801131), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487) and OGG1 Ser326Cys (rs1052133). Allelic, genotypic and haplotype association analyses with disease risk and clinicopathological parameters were performed.ResultsA nominally significant association with breast cancer risk was observed for MTHFR C677T polymorphism heterozygous genotype in the codominant model (OR: 0.57, 95% CI: 0.32–1.00, p = 0.049) and for Cys/Cys genotype of the OGG1 Ser326Cys polymorphism in the recessive model (OR: 0.23, 95% CI: 0.05–1.11, p = 0.0465). No significant differences were found at genotype-level for A1298C polymorphism of the MTHFR gene and Arg194Trp and Arg399Gln of the XRCC1 gene. Furthermore, the OGG1 and XRCC1 rs25487 polymorphisms were nominally associated with PgR, Her2 status and with sporadic breast cancer, respectively.ConclusionsBased on genetic characteristics of individuals included in this study, results suggest that MTHFR CT and OGG1 Cys/Cys genotypes have a protective effect that may have an influence on breast cancer risk in a representative Northern Sardinian population.

DNA repair gene OGG1 polymorphism and its relation with oxidative DNA damage in patients with Alzheimer’s disease

There is considerable evidence that oxidative DNA damage is increased, DNA repair capacity is decreased in patients with Alzheimer’s disease. Base excision repair is the major pathway in removal of oxidative DNA damage. 8-oxo-deoxyguanosine DNA glycosylase 1 (OGG1) is the enzyme which is involved in the first step of this repair process. Alterations in DNA repair capacity may be related with polymorphisms in DNA repair genes. In order to investigate the effect of OGG1 Ser326Cys polymorphism on oxidative DNA damage level, OGG1 genotyping was performed, basal and oxidative DNA damage in lymphocytes and 8-OHdG level in plasma were examined in patients with Alzheimer’s disease. Basal and oxidative DNA damage and 8-OHdG level were measured by OGG1-modified comet assay and enzyme-linked immunoassay, respectively. OGG1 genotyping was performed by polymerase chain reaction- restriction fragment length polymorphism assay. Basal and oxidative DNA damage and plasma 8-OHdG levels were found to be higher in the Alzheimer’s disease group than those in the control group (P < 0.001). In the Alzheimer’s disease group, the levels of oxidative DNA damage was higher in the patients having OGG1 (Ser326Cys + Cys326Cys) genotype than those in the patients having OGG1 Ser326Ser genotype. It was concluded that oxidative DNA damage is increased in patients with Alzheimer’s disease and OGG1 Ser326Cys polymorphism may be responsible for this increase.

Urinary 8-hydroxydeoxyguanosine in relation to XRCC1 rs25487 G/A (Arg399Gln) and OGG1 rs1052133 C/G (Ser326Cys) DNA repair genes polymorphisms in patients with chronic hepatitis C and related hepatocellular carcinoma.

Background and aim: DNA repair represents a protective mechanism against cell injury and cancer. 8-hydroxy-deoxyguanosine (8-OHdG) is the main ROS-induced DNA mutation. The current study aimed to evaluate urinary 8-OHdG levels in patients with chronic hepatitis C virus (HCV) and its related hepatocellular (HCC) and correlate its level to XRCC1 rs25487 G/A and OGG1 rs1052133 C/G gene polymorphisms.Materials and methods: Urinary 8-OHdG assays were performed using HPLC technique, and XRCC1 rs25487 G/A and OGG1 rs1052133 C/G gene polymorphisms were analyzed by PCR using confronting two-pair primer method (PCR-CTPP) in 200 subjects allocated into 50 chronic HCV patients, 50 HCV-related HCC patients, and 100 controls.Results: There were significantly increased urinary 8-OHdG levels in HCV-related HCC and chronic HCV patients when compared with the controls (P<0.05 for all). Urinary 8-OHdG was associated with the tumor spread. Regarding, XRCC1 (Arg399Gln), AA (Gln/Gln) genotype and A-allele were more frequent in HCC and chronic HCV patients than in the controls (P<0.05). ORs (95%CI) using the dominant and the recessive genetic models were; 2.1 (1.1–4.1), P=0.032 and 1.9 (1–3.6), P=0.043 respectively. For OGG1 (Ser326Cys), GG (Cys/Cys) genotype and G-allele were increased significantly in chronic HCV and HCC patients compared to the controls (P<0.05). ORs (95%CI) under the dominant and the recessive genetic models were; 2.1 (1.1–4.1), P=0.032 and 1.9 (1–3.8), P=0.049 respectively. Additionally, XRCC1 (AA) and OGG1 (GG) genotypes had significantly increased urinary 8-OHdG levels among patients (P<0.05).Conclusions: XRCC1 (AA) and OGG1 (GG) could be considered as possible genotypic risk factors for HCV- related HCC development which were associated with significantly high urinary 8-hydroxy-deoxyguanosine levels, thus urinary 8-OHdG could be considered as non-invasive marker in follow-up chronic HCV progression into HCC.

Impact of polymorphism in DNA repair genes OGG1 and XRCC1 on seminal parameters and human male infertility

The DNA repair capacity in the mature spermatozoa is highly compromised due to the base-excision repair (BER) route being truncated. In the mature spermatozoa, only the first enzyme of the route (OGG1) is present. Consequently, reduced activity of the enzymes of the BER route both during spermatogenesis and in the mature spermatozoa may be detrimental for fertility. The objective of our study was to investigate the correlation between two representative SNPs of those enzymes, SNPs OGG1 Ser326Cys (rs1052133) and XRCC1 Arg399Gln (rs25487) and male infertility. A total of 313 seminal samples from infertile patients and 80 from donors with proven fertility were included in the study. All samples were subjected to a regular sperm analysis and genotyped using the PCR-RFLP system. We found significant differences in the genotype frequencies between patients and donors for the XRCC1 Arg399Gln polymorphism (χ2(2)=8.7, p=0.013), with the Gln allele showing a protective role and for the OGG1 Ser326Cys polymorphism between normozoospermic and non-normozoospermic patients (χ2(2)=12.67, p=0.002) with the Cys allele showing a detrimental effect over concentration. In conclusion, our study shows that polymorphisms in the genes coding for the DNA damage repair enzymes may be associated with poor sperm parameters and male infertility.

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.

OGG1 Ser326Cys polymorphism, HIV, obesity and air pollution exposure influences adverse birth outcome susceptibility, within South African Women

The global HIV and obesity epidemics are major public health concerns; particularly as both are associated with increased risk of adverse birth outcomes. Despite extensive research, their combined effect, in terms of birth outcomes, has not been investigated. A single-nucleotide polymorphism (SNP) within 8-oxoguanine glycosylase 1 (OGG1) (Ser326Cys) has been suggested to affect body mass indices and therefore could predispose South African (SA) women to adverse effects of obesity. This study investigated the associations of OGG1 Ser326Cys SNP in relation to HIV and obesity on the susceptibility of low-birthweight (LBW) and pre-term birth (PTB) in SA women exposed to ambient air-pollution living in Durban. In our study population, the OGG1 SNP was associated with HIV and obesity. Wild-type (CC)-carrying patients had increased susceptibility for HIV-associated LBW and PTB. Co-morbid HIV and obese patients delivered neonates with decreased birthweights. Living within the heavily-polluted south-Durban and carrying the CC-genotype increased the risk for PTB within our study population.