Xeroderma Pigmentosum Complementation Group D Research Articles

Impact of XRCC3 rs861539 and XPD rs13181 gene polymorphisms on childhood acute lymphoblastic leukemia in Egyptian patients

Abstract Background There is mounting evidence that the genotypes of DNA repair proteins and susceptibility to certain malignancies are related. Few studies, however, have examined the role of the homologous repair gene X-ray repair cross-complementing group 3 (XRCC3) genotype and xeroderma pigmentosum complementation group D (XPD) in the development or prognosis of acute lymphoblastic leukaemia (ALL). Aim of the study In this study, we investigated the impact of XRCC3 rs861539 and XPD rs13181 polymorphisms on the risk of ALL. To the best of our knowledge, this is the first report of XRCC3 and XPD polymorphisms in ALL Egyptian patients. Methods Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was used to analyse XRCC3 rs861539 and XPD rs13181 gene polymorphisms in 96 patients with ALL and in 103 disease-free controls, who were of a similar age. Results ALL risk is lower in individuals with the homozygous variant TT genotype at XRCC3 rs861539. The heterozygous variant CT genotype of XRCC3 was connected to increased disease risk of ALL in males. Additionally, C allele frequency was noticeably higher than T allele frequency in pre B ALL. In this investigation, there was no correlation between the XPD Lys751 rs13181 polymorphism and risk of ALL. Conclusion Our research reveals that genetic variation in the genes for DNA repair may influence ALL susceptibility.

Nephrotoxic effect of heavy metals and the role of DNA repair gene among secondary aluminum smelter workers

This study aims to estimate the association between some heavy metals in suspended particulate matter (SPM) and kidney damage among workers at different departments in a secondary aluminum production plant. It also investigates the association between Xeroderma Pigmentosum complementation group D (XPD) gene polymorphisms and worker’s susceptibility to kidney dysfunction. It was conducted on 30 workers from the administrative departments and 147 workers from different departments in the production line. Estimation of some heavy metals (Al, Co, Ni, Cu, Pb, and Cd) in suspended particulate matter (SPM) is done. Also, urinary levels of those metals were measured for all workers. Kidney injury molecule 1 (KIM-1), clusterin levels, and XPD protein level were estimated. Genotyping of XPD gene polymorphisms was performed. The measured annual average concentrations of the estimated heavy metals were lower than the permissible limits. Gravity area had the maximum concentration of metals with a higher Al average daily dose and hazardous index > 1. Kidney injury biomarkers (clusterin and KIM-1) were increased significantly (p < 0.05) while XPD protein showed the lowest levels among workers at the gravity and cold rolling areas. XPD Asn/Asp genotype was more dominant among those workers (85.7%). Conclusion: aluminum workers are at risk of kidney disorders due to heavy metal exposure. The individual’s susceptibility to the diseases is related to the DNA repair efficiency mechanisms. The defect in XPD protein represents a good indicator of susceptibility to the disease. KIM-1 and clusterin estimation is a predictor biomarker for early-staged kidney diseases.

Abstract 3747: RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers

Abstract Ribosomal protein S3 (rpS3) is a multifunctional protein working in translation, DNA repair, cancer, apoptosis etc. UV induced DNA damage is repaired by the nucleotide excision repair (NER) pathways; defects in these pathways lead to a genetic instability known as xeroderma pigmentosum (XP) eventually developing skin cancers. We discovered that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. Here, we showed that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV through XPD and rpS3 interaction thus augmenting the helicase activity of XPD protein. Additionally, the knockdown of rpS3 caused reduced NER efficiency and the subsequent addition of rpS3 restored the helicase activity of the TFIIH complex in cells. We present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We also propose that rpS3 is a novel accessory protein of the NER pathway and its recruitment to the repair machinery upon UV damage augments repair efficiency by enhancing XPD helicase function and increasing its turnover rate, thus facilitating DNA repair. In addition to this, manipulations of rpS3 gene could complement XP-D phenotype and prevent UV damage and skin cancer occurrence. Animal studies strongly indicate that these result could be applied not only for the development of cancer drugs but also for cosmeceuticals. [1] FASEB J. (2020) 34: 8102 [2] Cell &amp; Mol Life Sci (2021) 78: 3591 Citation Format: Joon Kim, Yong-Joon Park, Tae Sung Kim, Woo Sung Ahn, Hag Dong Kim. RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3747.

In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W).

Xeroderma pigmentosum complementation group D (XPD) is a UV-sensitive syndrome and a rare incurable genetic disease which is caused by the genetic mutation of the excision repair cross-complementation group 2 gene (ERCC2). Patients who harbor only XPD R683W mutant protein develop severe photosensitivity and progressive neurological symptoms. Cultured cells derived from patients with XPD (XPD R683W cells) demonstrate a reduced nucleotide excision repair (NER) ability. We hope to ameliorate clinical symptoms if we can identify candidate agents that would aid recovery of the cells’ NER ability. To investigate such candidates, we created in silico methods of drug repurposing (in silico DR), a strategy that utilizes the recovery of ATP-binding in the XPD R683W protein after the induced fit. We chose 4E1RCat and aprepitant as the candidates for our in silico DR, and evaluated them by using the UV-induced unscheduled DNA synthesis (UDS) assay to verify the recovery of NER in XPD R683W cells. UDS values of the cells improved about 1.4–1.7 times after 4E1RCat treatment compared with solvent-only controls; aprepitant showed no positive effect. In this study, therefore, we succeeded in finding the candidate agent 4E1RCat for XPD R683W. We also demonstrated that our in silico DR method is a cost-effective approach for drug candidate discovery.

Ribosomal protein S3 associates with the TFIIH complex and positively regulates nucleotide excision repair.

In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.

The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine-Mediated Neuronal DNA Damage.

Bupivacaine, a local anesthetic widely used for regional anesthesia and pain management, has been reported to induce neuronal injury, especially DNA damage. Neurons employ different pathways to repair DNA damage. However, the mechanism underlying bupivacaine-mediated DNA damage repair is unclear. A rat neuronal injury model was established by intrathecal injection of (3%) bupivacaine. An in vitro neuronal injury model was generated by exposing SH-SY5Y cells to bupivacaine (1.5 mmol/L). Then, a cDNA plate array was used to identify the DNA repair genes after bupivacaine exposure. The results showed that xeroderma pigmentosum complementary group D (XPD) of the nuclear excision repair (NER) pathway was closely associated with the repair of DNA damage induced by bupivacaine. Subsequently, Western blot assay and immunohistochemistry indicated that the expression of the repair enzyme XPD was upregulated after DNA damage. Downregulation of XPD expression by a lentivirus aggravated the DNA damage induced by bupivacaine. In addition, phosphatidyl-3-kinase (PI3K)/AKT signaling in neurons was inhibited after exposure to bupivacaine. After PI3K/AKT signaling was inhibited, bupivacaine-mediated DNA damage was further aggravated, and the expression of XPD was further upregulated. However, knockdown of XPD aggravated bupivacaine-mediated neuronal injury but did not affect PI3K/AKT signaling. In conclusion, the repair enzyme XPD, which was partially regulated by PI3K/AKT signaling, responded to bupivacaine-mediated neuronal DNA damage. These results can be used as a reference for the treatment of bupivacaine-induced neurotoxicity.

Polymorphisms in XPC and XPD genes modulate DNA damage in pesticide-exposed agricultural workers of Punjab, North-West India.

The genetic susceptibility of individuals to the genotoxic effect of pesticides may be modulated by variations in genes involved in nucleotide excision repair (NER) pathway and therefore plays an important role in the evaluation of occupational risk. We aimed to evaluate the role of xeroderma pigmentosum complementation group C (XPC) Lys939Gln (A2920C, rs2228001), XPC Ala499Val (C2151T, rs2228000), xeroderma pigmentosum complementation group D (XPD) Asp312Asn (G23591A, rs1799793) and XPD Lys751Gln (A35931C, rs13181) in the modulation of DNA damage. A total of 450 subjects (225 pesticide-exposed agricultural workers and 225 age- and sex-matched controls) from Punjab, North-West India were recruited to study DNA damage by alkaline comet assay. Genotyping was carried out by PCR-RFLP using site-specific restriction enzymes. We found significant elevation in DNA damage parameters in pesticide-exposed agricultural workers as compared to the controls (p < 0.01). Association of comet tail length with XPC 939Gln/Gln (CC), XPD 312Asp/Asn (GA) and XPD 312Asn/Asn (AA) genotypes was observed. Frequency of cells showing DNA migration was significantly higher in exposed workers with variant XPC 939Gln/Gln (CC), XPD 312Asp/Asn (GA) and XPD 312Asn/Asn (AA) genotypes. Mean tail length was significantly increased in agricultural workers carrying XPD 312Asn/Asn (AA) genotype. Elevation in total comet DNA migration was also observed in exposed workers carrying variant XPC 939Lys/Gln (AC), XPC 939Gln/Gln (CC), XPC 499Val/Val (TT) and XPD 312Asn/Asn (AA) genotypes. Our results strongly indicate significant positive association of variant XPC and XPD genotypes with higher pesticide-induced DNA damage in North-West Indian agricultural workers.

Contribution of xeroderma pigmentosum complementation group D gene polymorphisms in breast and ovarian cancer susceptibility: A protocol for systematic review and meta analysis.

Background:The role of xeroderma pigmentosum complementation group D (XPD) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive systemic review and meta-analysis to better clarify the association.Methods:Relevant case-control studies published in electronic data base from October 1999 to September 2019 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) were calculated by using Revman 5.2 software (Cochrane Collaboration, Copenhagen).Results:31 articles including 38 case-control studies and 2 XPD polymorphisms (rs1799793 and rs238406) were analyzed. The results showed statistical significance in heterozygous mutants among Asian population for rs1799793 (GA vs GG + AA: OR = 1.38, 95%CI = 1.21–1.56), and Caucasian population for rs238406 (CA vs AA + CC: OR = 0.63, 95%CI = 0.49–0.80), while the rest comparisons including overall groups and subgroups stratified by cancer types and ethnicity failed to indicate any association with breast and ovarian cancer risk.Conclusions:The current meta-analysis suggested no concrete correlation of XPD rs1799793(G/A) and rs238406(C/A) polymorphisms with breast cancer or ovarian cancer susceptibility. However, it indicated that heterozygous genotypes might share different pathophysiologic mechanism from not only homozygous wildtypes but also homozygous mutants. More case–control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.

XPD inhibits cell growth and invasion and enhances chemosensitivity in esophageal squamous cell carcinoma by regulating the PI3K/AKT signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is a lethal disease due to its high aggressiveness. The aim of the present study was to investigate the role of xeroderma pigmentosum complementation group D (XPD) in the growth and invasion of ESCC and to elucidate the potential underlying molecular mechanisms. Western blot analysis and RT-qPCR were used to detect the expression level of XPD in ESCC tissue samples and adjacent normal esophageal tissue samples. The pEGFP-N2/XPD plasmid was transfected into human ESCC cell lines (EC9706 and EC109). The proliferation, apoptosis, migration and invasion of EC9706 or EC109 cells were assessed following transfection with the XPD overexpression plasmid. The chemosensitivity of EC9706 or EC109 cells to cisplatin or fluorouracil was evaluated by CCK-8 assay. The expression levels of phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor (NF)-κB, Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling pathway-related genes were detected by RT-qPCR and western blot analysis. The results demonstrated that the expression level of XPD was markedly lower in ESCC tissue samples than in adjacent normal esophageal tissue samples. The pEGFP-N2/XPD plasmid was successfully transfected into EC9706 or EC109 cells, inducing XPD overexpression. A High XPD expression markedly suppressed cell proliferation, migration and invasion, and increased the apoptotic rate of EC9706 and EC109 cells. Furthermore, the overexpression of XPD significantly increased the chemosensitivity of EC9706 and EC109 cells to cisplatin or fluorouracil. Following XPD overexpression, the expression levels of PI3K, p-AKT, c-Myc, Cyclin D1, Bcl-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 were markedly downregulated, while the expression level of p21 was markedly upregulated. On the whole, the findings of the present study demonstrate that XPD inhibits the growth and invasion of EC9706 and EC109 cells, whilst also enhancing the chemosensitivity of EC9706 and EC109 cells to cisplatin or fluorouracil by regulating the PI3K/AKT signaling pathway. XPD may thus be an underlying target for ESCC treatment and drug resistance.

Association of polymorphisms of xeroderma pigmentosum complementation group D gene with cervical cancer in Maharashtrian population: A case-control study

Background: Maharashtrian population is at the risk of cervical cancer (CC) and is not subjected to investigate the cancer susceptibility in association with genetic determinants. Objectives: This study was aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in DNA repair gene xeroderma pigmentosum complementation group D (XPD) with CC risk from rural Maharashtra. Materials and Methods: We used polymerase chain reaction and-restriction fragment length polymorphism to analyze SNPs in XPD gene from 350 patients with CC and 400 age and sex-matched disease-free controls. Results: The results indicated no significant difference in the genotype distribution between CC patients and controls for the XPD gene at codon 156 of exon 6 and codon 751 of exon 23, but the results showed that allele frequencies of XPD Asn 312 of codon 312 of exon 10 (odds ratio = 0.31; 95% confidence intervals = [0.16–0.63]; P =

Genetic polymorphisms may influence the vertical growth rate of melanoma.

Background: Identification of new predictive markers in melanoma is of great clinical importance. This study was aimed to analyze association between selected common variants in the cancer susceptibility genes and melanoma progression at the time of diagnosis.Material and Method: The study included 243 consecutive patients with melanoma. Genotyping was performed using real-time PCR.Results: Our data revealed modest association between xeroderma pigmentosum complementation group D (XPD) codon 312 polymorphism and tumor thickness (as defined by Breslow score; XPD D312N CC: 3.00 ± 3.78mm, CT: 1.71 ± 2.48mm, TT: 2,53 ± 3,24mm, P=0.023). The CT genotype in XPD D312N polymorphism was more frequently represented in non-invasive melanomas compared to deeply penetrating tumors. None of the common SNPs in cyclin dependent kinase inhibitor 2A (CDKN2A), vitamin D receptor (VDR), melanocortin 1 receptor (MC1R) were associated with Breslow depth.Conclusion: These findings suggest that genetic alteration in XPD contributes to melanoma progression and may be a potential diagnostic and molecular prognostic marker.

Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy.

The study investigated role of xeroderma pigmentosum complementation group D (XPD) single nucleotide polymorphisms in modulating lung cancer risk and its association with overall survival and clinical outcomes. XPD polymorphisms were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). CC genotype of A751Cpolymorphism was associated with an increased lung cancer risk (p=0.01). Classification and Regression Tree (CART) analysis depicted C156A as the major contributing factor. Patients having CC, treated with irinotecan-cisplatin/carboplatin regimen showed a better survival (median survival time =25.2) whereas a poor survival was for XPD G312A. Similarly, patients treated with pemetrexed and carrying heterozygous genotype of G312Apolymorphism had a poor survival (p=0.01). A751C and G312A act as a predictive marker in lung cancer patients treated with platinum chemotherapy. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patient. [Formula: see text].

Dynamics of DNA unwinding by helicases with frequent backward steps

XPD (Xeroderma pigmentosum complementation group D) is a prototypical 5′ – 3′ translocating DNA helicase that exhibits frequent backward steps during DNA unwinding. Here, we propose a model of DNA unwinding by XPD. With the model we explain why XPD exhibits frequent backsteps while other helicases show rare backsteps. We explain quantitatively the single-molecule data on probability of –1-bp step and mean dwell time of one step versus ATP concentration for XPD at fixed large external force applied to the ends of the DNA hairpin to unzip the hairpin. We study DNA unwinding velocity, probability of –1-bp step and mean dwell time of one step for XPD versus external force at various ATP concentrations. We compare DNA unwinding dynamics of the 5′ – 3′ helicase XPD with that of 3′ – 5′ helicase RecQ. Our results show that the DNA unwinding velocity of XPD is sensitively dependent on the external force, which is contrast to RecQ that shows insensitive dependence of DNA unwinding velocity on the external force, explaining the experimental data showing that RecQ is an “optimally active” helicase while XPD is a “partially active” helicase. The DNA unwinding dynamics of different helicases under the external force is also studied.

XRCC1 and XPD polymorphisms and their relation to the clinical course in hepatocarcinoma patients.

In this study genotyping of hepatocellular carcinoma (HCC) patients was conducted to detect polymorphisms on the X-ray repair cross-complementing 1 (XRCC1) and xeroderma pigmentosum complementary group D (XPD) genes and analyze the relationship of their presence with the clinical features of the cancer. A total of 172 patients with HCC were selected in Qilu Hospital, Shandong University, from January 2010 to September 2011. All patients underwent resection of HCC and no tumor metastases were found. Peripheral venous blood samples (3–5 ml) were collected from the patients to extract genomic DNA. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing. During the five-year follow-up, the survival of patients with various genotypes of XRCC1 and XPD genes were observed and compared. Logistic regression analysis was used to analyze the association between single nucleotide polymorphisms of XRCC1 and XPD genes and the prognosis of patients with HCC. χ2 tests showed that XRCC1-194, XRCC1-280 and XPD-312 gene polymorphisms were significantly correlated with the number, location and diameter of the tumors (p<0.05). No significant difference was found in the survival curve of patients presenting different genotypes of the XRCC1-194 locus (p>0.05). Nevertheless, a significant difference was found in the survival curve of patients with AA and GG genotypes of the XRCC1-280 locus and in the patients with AA, GA and GG genotypes of the XPD-312 locus (p<0.05). Logistic regression analysis showed that the XRCC1-194 genotype was not an independent risk factor for HCC mortality risk (p>0.05), but XRCC1-280 (OR=1.815, p<0.01) and XPD-312 (OR=1.815, p<0.01) genotypes were independent risk factors for a poor prognosis. Taken together our results point to polymorphisms in XRCC1 and XPD genes as being related to the clinical characteristics of HCC, making them suitable prognostic markers of HCC.

Investigation of DNA repair genes XPD and hOGG1 in type 2 Diabetes mellitus

Increased oxidative stress in type 2 diabetes cause to the accumulation of DNA damage and results diabetic complications. Xeroderma pigmentosum complementation group D (XPD) and human oxoguanine glycosylase 1 (hOGG1) are genes involved in the repair of oxidative DNA damage. In this study, we aimed to evaluate association between XPD Lys751Gln and hOGG1 Ser326Cys polymorphisms with type 2 diabetes mellitus (T2DM) in the Turkish population. Seventy-one T2DM patients and 54 healthy individuals were incorporated into this study. DNA was extracted from whole blood. The Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP) techniques were used. There was statistically significant difference between patient and control groups in the genotype distribution of XPD Lys751Gln polymorphism (p˂0.05). While the Lys/Lys genotype was found significantly higher in control group, the Lys/Gln was higher in patients. (p˂0.05). There was no significant difference between groups in the genotype distribution of hOGG1 Ser326Cys polymorphism. Despite the small number of subjects included in the study, it could be interpreted that the Lys/Gln genotype of XPD Lys751Gln polymorphism may be contributing to the development of diabetes.

Increased Oxidative Damage and Reduced DNA Repair Enzyme XPD Involvement in High Glucose-Mediated Enhancement of Levobupivacaine-Induced Neurotoxicity.

Levobupivacaine is one of the major clinical local anesthetics, but it can cause neuron toxic damage. Hyperglycemia can cause neuronal DNA oxidative damage and inhibit expression of the DNA repair gene Xeroderma pigmentosum complementation group D (XPD). This study was designed to determine whether high glucose levels inhibit XPD expression and enhance levobupivacaine-induced DNA damage. We evaluated XPD mRNA and protein expression in SH-SY5Y cells after glucose and levobupivacaine exposure. We next investigated cells reactive oxygen species (ROS) levels, DNA damage and apoptosis with redox-sensitive fluorescent dye DCFH-DA (2',7'-dichlorofluorescein diacetate), comet assays, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferased UTP nick end labeling) assays. XPD expression was inhibited in cells exposed to prolonged high glucose with a concomitant increase in ROS production and more severe DNA damage compared to control culture conditions, and these changes were further exacerbated by levobupivacaine. Our findings indicate that subjects with diabetes may experience more detrimental effects following local anesthetic use.

XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma susceptibility: A meta-analysis of 11 case-control studies in an Asian population.

This meta-analysis was performed to evaluate the association between xeroderma pigmentosum complementary group D (XPD) Lys751Gln and Asp312Asn polymorphisms and susceptibility to hepatocellular carcinoma (HCC). PubMed, Embase, Google Scholar and the Chinese National Knowledge Infrastructure and the Chinese Biomedicine databases were systematically searched to identify relevant studies published up to June 1, 2014. Statistical analyses were performed using Stata version 12.0 software. A total of 11 case-control studies, comprising 2,852 cases and 2,936 controls, were included. The results of the meta-analysis revealed that a significant association between the risk of HCC and variant genotypes of the XPD Lys751Gln and Asp312Asn polymorphisms was evident in the homozygote comparison [Gln/Gln versus Lys/Lys: Odds ratio (OR), 1.831; 95% confidence interval (CI), 1.001-3.349], heterozygote comparison (Lys/Gln versus Lys/Lys: OR, 1.486; 95% CI, 1.044-2.114), dominant model (Gln/Gln + Lys/Gln versus Lys/Lys: OR, 1.540; 95% CI, 1.054-2.249) and allelic contrast (Gln-allele versus Lys-allele: OR, 1.453; 95% CI, 1.032-2.046) for the Lys751Gln polymorphism and the homozygote comparison for the Asp312Asn polymorphism (Asn/Asn versus Asp/Asp: OR, 1.352; 95% CI, 1.010-1.808). By contrast, no significant association was observed in the recessive model for the Lys751Gln polymorphism (Gln/Gln versus Lys/Gln + Lys/Lys: OR, 1.603; 95% CI, 0.924-2.779), or for the heterozygote comparison (Asn/Asp versus Asp/Asp: OR, 1.229; 95% CI, 0.857-1.762), dominant model (Asn/Asn + Asp/Asn versus Asp/Asp: OR, 1.249; 95% CI, 0.910-1.715), recessive model (Asn/Asn versus Asp/Asn + Asp/Asp: OR, 1.250; 95% CI, 0.940-1.663) or allelic contrast (Asn-allele versus Asp-allele: OR, 1.226; 95% CI, 0.965-1.557) for the Asp312Asn polymorphism. The present meta-analysis has indicated that the XPD Lys751Gln polymorphism could be a potential biomarker of HCC susceptibility and that the XPD Lys751Gln and Asp312Asn polymorphisms could be risk factors for HCC susceptibility in an Asian population; however, further large-scale and well-designed studies are required to reach a more precise and comprehensive conclusion.

Association of the Asp312Asn and Lys751Gln polymorphisms in the XPD gene with the risk of non-Hodgkin's lymphoma: evidence from a meta-analysis.

Polymorphisms in DNA repair genes may alter DNA repair capacity and, consequently, lead to genetic instability and carcinogenesis. Several studies have investigated the association of the Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementation group D (XPD) gene with the risk of non-Hodgkin’s lymphoma (NHL), but the conclusions have been inconsistent. Therefore, we performed this meta-analysis to more precisely estimate these relationships. A systematic literature search was performed using the PubMed, Embase, and Chinese Biomedical (CBM) databases. Ultimately, 6 studies of Asp312Asn, comprising 3,095 cases and 3,306 controls, and 7 studies of Lys751Gln, consisting of 3,249 cases and 3,676 controls, were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of each association. Overall, no association was observed between the Asp312Asn polymorphism and NHL risk (homozygous: OR = 1.11, 95% CI = 0.94-1.32; heterozygous: OR = 1.00, 95% CI = 0.89-1.11; recessive: OR = 1.12, 95% CI = 0.95-1.31; dominant: OR = 1.02, 95% CI = 0.92-1.13; and allele comparison: OR = 1.04, 95% CI = 0.96-1.12) or between the Lys751Gln polymorphism and NHL risk (homozygous: OR = 0.97, 95% CI = 0.83-1.15; heterozygous: OR = 0.96, 95% CI = 0.86-1.06; recessive: OR = 1.00, 95% CI = 0.86-1.16; dominant: OR = 0.96, 95% CI = 0.87-1.06; and allele comparison: OR = 0.98, 95% CI = 0.91-1.05). Furthermore, subgroup analyses did not reveal any association between these polymorphisms and ethnicity, the source of the controls, or the NHL subtype. These results indicated that neither the Asp312Asn nor Lys751Gln XPD polymorphism was related to NHL risk. Large and well-designed prospective studies are required to confirm this finding.

DNA repair genes XPD and XRCC1 polymorphisms and risk of end-stage renal disease in Egyptian population

DNA repair gene polymorphisms may affect DNA repair capacity and modulate susceptibility to end-stage renal disease (ESRD). We aimed to determine the association of polymorphisms in xeroderma pigmentosum complementation group D (XPD) and X-ray cross-complementing group 1 (XRCC1) with ESRD development. Polymorphisms in XPD codons 312 and 751 and XRCC1 codon 399 were genotyped in 98 patients undergoing hemodialysis and 102 healthy controls using polymerase chain reaction and restriction fragment length polymorphism. Patients having XRCC1-399 Arg/Gln genotype or XRCC1-399 Gln/Gln genotype had a significantly higher risk of ESRD than those with XRCC1-399 Arg/Arg [odds ratio (OR): 2.48; 95% confidence intervals (CI): 1.36–4.52; p = 0.004 and OR: 4.05; 95% CI: 1.19–13.73; p = 0.03, respectively]. We also found a significantly higher frequency of the XRCC1 399Gln allele in patients with ESRD than in controls (OR: 2.22; 95% CI: 1.16–4.25; p = 0.02). Combination of the Arg/Gln or Gln/Gln genotypes of XRCC1 Arg399Gln polymorphism with Asp/Asn or Asn/Asn genotypes of XPDAsp312Asn or with the Lys/Gln or Gln/Gln genotypes of XPD Lys751Gln was significantly associated with the development of ESRD. Haplotypes association showed that association of Gln allele of XRCC1 Arg399Gln polymorphism with the Asn allele of XPDAsp312Asn polymorphism (p = 0.004) or Gln allele of XRCC1 Arg399Gln polymorphism with the Gln allele of XPD Lys751Gln polymorphism (p = 0.003) was highly significantly associated with the development of ESRD. This study revealed that XRCC1 Arg399Gln polymorphism may confer increased risk for the development of ESRD. Furthermore, larger studies should be conducted to confirm these results.

Polymorphisms of DNA Repair Genes XPD (Lys751Gln) and XRCC1 (Arg399Gln), and The Risk of Age-Related Cataract: A Meta-Analysis

Purpose: A meta-analysis of available studies was used to test the association between two DNA repair genes and age-related cataract.Materials and Methods: A systematic search of the Chinese National Knowledge Infrastructure, EMBASE and PubMed databases identified six studies that were analyzed. Meta-analysis was used to evaluate single nucleotide polymorphisms (SNP) of the DNA repair gene xeroderma pigmentosum complementation group D (XPD) (Lys751Gln) and the X-ray repair cross-complementing gene 1 (XRCC1) (Arg399Gln). Only articles published before June 6, 2014, were included. The quality of the studies was determined using Newcastle–Ottawa Scale tools. The summary odds ratio (OR) and corresponding confidence interval (CI) for XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms and risk of age-related cataract were estimated by random and fixed-effects models. Sensitivity analysis was employed to determine the robustness of the conclusions.Results: Six studies, with a total of 1518 patients with cataractous lenses and 1437 subjects with clear lenses, were included in the meta-analysis. XRCC1 Arg399Gln polymorphisms were associated with cataract risk (recessive model: ORfixed = 0.79, 95% CI: 0.67–0.93; dominant model: ORfixed = 0.84, 95% CI: 0.64–1.11; additive model: ORfixed = 0.82, 95% CI: 0.72–0.92). Analysis of Chinese, but not non-Chinese subgroups, confirmed this association. The OR of XPD Lys751Gln polymorphisms for cataract was not significant. The associations remained significant after sensitivity analysis.Conclusions: This meta-analysis indicates that XRCC1 Arg399Gln polymorphisms, but not XPD Lys751Gln polymorphisms, are associated with risk of age-related cataract.