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 Table of Contents  
Year : 2019  |  Volume : 44  |  Issue : 2  |  Page : 128-133

The frequency of the DNA repair gene XRCC1 Arg399Gln polymorphism in Saudi Arabian and other ethnic groups and the risk of leukemias

Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia

Date of Submission15-May-2019
Date of Acceptance21-Aug-2019
Date of Web Publication15-Nov-2019

Correspondence Address:
Raed A Alharbi
Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha 1988, 58966
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejh.ejh_17_19

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Background The mutations and polymorphisms of the X-ray repair cross-complementing group 1 (XRCC1) gene may render base excision repair pathway ineffective, leading to cancers including leukemias. The variable occurrence of XRCC1 Arg399Gln polymorphism affects diverse ethnic groups differently; however, there is a lack of data for the Saudi population. This study sought to elucidate the allelic distribution and the frequency of XRCC1 Arg399Gln polymorphism in Saudi Arabian population and also to compare the same with other populations globally.
Materials and methods PubMed (Medline) and other relevant web-databases were used to extract published epidemiological studies conducted in diverse racial/ethnic groups.
Results The frequency of XRCC1 Arg399Gln variant allele (A) was found to be 25%. A significant difference was found for the UK (P<0.0001), Turkey (P≤0.001), Austria (P=0.009), Ukraine (P=0.008), Poland (P≤0.001), India (P≤0.001), and Romania (P=0.015) population, upon comparison of this frequency with that of other populations.
Conclusion The findings of this study show a unique pattern of DNA repair gene XRCC1 Arg399Gln variant allele in Saudi Arabia population possibly because of ethnic variation. The results may help in risk evaluation of individuals having exposure to environmental carcinogens and an eventual leukemia susceptibility in diverse populations.

Keywords: leukemia, polymorphism, X-ray repair cross-complementing group 1

How to cite this article:
Alharbi RA. The frequency of the DNA repair gene XRCC1 Arg399Gln polymorphism in Saudi Arabian and other ethnic groups and the risk of leukemias. Egypt J Haematol 2019;44:128-33

How to cite this URL:
Alharbi RA. The frequency of the DNA repair gene XRCC1 Arg399Gln polymorphism in Saudi Arabian and other ethnic groups and the risk of leukemias. Egypt J Haematol [serial online] 2019 [cited 2022 Sep 30];44:128-33. Available from: http://www.ehj.eg.net/text.asp?2019/44/2/128/271078

  Introduction Top

Leukemias are a group of hematological heterogenous disorders involving leukemic stem cells, which are capable of self-renewal and differentiation like normal hematopoietic stem cells [1]. Leukemias are subclassified into four main groups based on the stage of the disease, acute or chronic leukemia, and the origin of the cells, myeloid or lymphoid cells [2]. Failure of the host DNA repair system to fix errors in the DNA is considered as one of the most important factors leading to the onset and progression of leukemia [3],[4].

The susceptibilities to cancer across individuals and populations can be based upon the genetic variations that influence host DNA repair mechanisms [5]. A single-nucleotide polymorphism (SNP) is a change in a single nucleotide located at a precise position in the genome occurring at more than 1% rate in a population [6]. SNPs render individuals variably susceptible to a host of diseases like sickle-cell anemia, β-thalassemia, cystic fibrosis, and cancers [7],[8] along with the severity of illness and the prognosis.

They are generally not overwhelmingly penetrant; however, their association analysis in cancer is pertinent [9]. The carcinogens, both endogenous and exogenous, influence an individual’s ability to repair DNA lesions. Certain SNPs may limit DNA repair capacity, rendering these individuals more susceptible to cancer than the people without them [10]. The research findings about interindividual genetic variations in diverse ethnicities may help to identify and discover candidate susceptibility alleles contributing to the onset and development of cancer.

The X-ray repair cross-complementing groups 1 (XRCC1) binds to DNA repair-related proteins and influences the base excision repair (BER) process [11],[12],[13]. Multiple reports have suggested that XRCC1-SNP Arg399Gln at codon 399 is linked with diminished capacity to remove DNA adducts eventually resulting in DNA damage caused by oxidation [14], possibly leading to cancer onset including leukemia.

The XRCC1, located on chromosome 9q13.2 having 17 exons, encodes a 633-amino acid protein that is critical to a multistep BER pathway to clear the ‘nonbulky’ base adducts as a result of methylation, oxidation, reduction, or fragmentation of bases owing to ionizing radiation or oxidative damage [15].

The XRCC1, a scaffolding protein, has three DNA repair enzymes, namely, DNA ligase III, DNA polymerase B, and poly ADP-ribose polymerase, which is a part of excision and recombinant repair pathways [16].

Codon 399 in exon 10 (Arg to Gln) polymorphism, located in the BRCT-I interaction domain in a poly (ADP ribose) polymerase binding region, is one of the many polymorphisms detected in XRCC1 gene [17]. An early report studying the null mutant mice with XRCC1 gene error showing the embryonic development arrest emphasized its importance [18]. Another study around the same time elucidated the association of codon 399 polymorphism with reduced DNA repair capability by compromising BER capacity [19], rendering an individual at high risk of developing many diseases including cancer [20].

This study detected the frequency distribution of the XRCC1 exon 10 Arg399Gln, G23591A, rs25487 polymorphism among normal healthy individuals from Saudi Arabia, and compared with multiple epidemiologic research conducted globally.

  Materials and methods Top

Prevalence of gene variants

PubMed (Medline), web of science, and EGEMS database were searched for reports having keywords ‘XRCC1’, ‘G23591A’, ‘rs25487,’ and ‘polymorphism’, limited to human subjects, published in any language. Case control or cohort studies, including genotype frequencies for the control population were included, whereas studies having only allele frequencies with no genotype frequencies were excluded.

For each of the eligible studies, characteristics including the name of the first author, the year of publication, ethnicity of participants, the number of controls, study type, the inclusion/exclusion criteria, and frequencies of alleles/genotypes of the participants were abstracted. The data from the most recent publication were used in case of more than one report from the same ethnicity.

Twenty-two studies [3],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41], about the prevalence of the XRCC1 exon 10 (G>A) polymorphism, were abstracted and included in this study and subsequently used for comparison with the Saudi Arabian population.

Data availability

The data supporting the findings of this study are available within the article.

Statistical analysis

SPSS (version 21) (IBM Corporation, Armonk, New York, USA) statistical software program was used for Pearson’s χ2-test for comparative analysis of the genotype and allelic frequencies of diverse populations. Court-Lab (web-based software program) was used to analyze Hardy–Weinberg equilibrium. P value of 0.05 was considered as statistically significant.

  Results Top

The genotype distribution of XRCC1 (exon 10, Arg>Gln) in Saudi Arabian population, which was in accordance with Hardy–Weinberg equilibrium, showed the minor allele frequency (MAF) at 25% ([Table 1]) [21]. The genotypic (Arg/Arg, Arg/Gln, and Gln/Gln) and allelic frequency distribution of the studied polymorphism among diverse populations showed different MAF ([Table 2]). A significantly different MAF was found for the UK (P<0.0001), Turkey (P≤0.001), Austria (P=0.009), Ukraine (P=0.008), Poland (P≤0.001), India (P≤0.001), and Romania (P=0.015) population, upon comparison of Saudi Arabian frequency with that of other populations.
Table 1 Observed and expected genotypic frequencies of X-ray repair cross-complementing group 1 Arg399Gln polymorphism in the control group

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Table 2 Genotype and allele frequency distribution of X-ray repair cross-complementing group 1 Arg399Gln gene variant in various populations and P values in comparison with Saudi Arabian population

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  Discussion Top

Latest genomic research studies enable us to find variations in the DNA sequence and using them to predict a person’s risk of particular diseases and response to certain medications. A number of reports have produced compelling evidences that genetic variations modulate the risk of environmental carcinogenesis. The genetic susceptibility can contribute to the development of human cancer and many recent reports have shown an association of SNPs with an increased cancer risk helping in detecting the effects of SNPs as candidate genes.

DNA repair genes play an important role in the maintenance of genomic integrity and thus have been the target of lots of studies. The results suggest that inherited mutations in these genes can render individuals to a very high risk for the onset and progression of cancer [42]. DNA repair gene polymorphism data from the healthy population are of critical importance owing to the established differences in the frequency distribution between diverse ethnic/racial groups. The results of such studies can lead to the evaluation of the detected genetic markers in the risk, expression, prognosis, or treatment of many diseases including cancers. Multiple research studies pertaining to DNA repair gene polymorphisms have elucidated their importance in identifying both interindividual and inter-racial differences in carcinogenesis [43].

A sequence of evolutionary events like migration, admixture, population isolation, selective pressure, and genetic drift have led to the global diversity of human genomes [44],[45],[46]. Genomic imprints conserved in the genomes of diverse population aid to understand health and disease [47],[48]. Recently, the HapMap project and the Human Genome Diversity Project have contributed significantly to evolve a single nucleotide change database, by recording the genetic variations present between individuals of an ethnic group as well as within different ethnicities, globally [49],[50],[51].

Genetic variation analysis of the Saudi population, presumably a diverse population, can lead to early prevention and intervention strategies. This study analyzed the frequency distribution of the XRCC1 exon 10 G>A genetic variant in Saudi population and compared it with that of different populations across the world.

The cell’s first line of defense is the repair of damaged DNA against cancer [52],[53]. The XRCC1 gene analyzed in this study significantly contributes to repair of both single-strand break and the base excision [54]. The XRCC1 knockout cells are genetically unstable and prone to DNA damage agents, including ionizing radiation, alkylating agents, ultraviolet light, and hydrogen peroxide [55],[56]. XRCC1 variants may lead to an increased sensitivity to ionizing radiation having prolonged cell cycle delay at stage G [57].

This study shows 25% frequency of variant allele (A) of exon 10 in Saudi population, which is significantly different from many other countries including the UK, Turkey, Austria, Ukraine, Poland, India, and Romania when compared with the Saudi population. It was found to be lower than UK, Turkey, Austria, Poland, Ukraine, Mexico, India and Romania, whereas the frequency was higher than what was observed in China, Egypt, and a cohort of India. Interestingly, the frequency distribution of the variant allele in Saudi population was found to be almost similar when compared with Thai population.

As mentioned earlier, most of the SNPs are less penetrant and diseases are polygenic in nature, thus different allele frequencies among independent data sets may affect the eventual SNP effect. In genetic-association studies, a small change of 0.02 in MAF can lead to major changes in statistical significance. Furthermore, in case of two interacting SNPs, the statistically significant independent effect of one SNP may reduce significantly with a change in allele frequency of less than 0.1 at the second interacting polymorphism [58].

The differences in allelic frequency in genetic-association studies can be based upon racial variation, heterogeneity of studied population, and variable sample sizes. Previous reports have showed the diverse patterns of DNA repair genes when compared with different populations, globally [59]. The variable prevalence of DNA repair SNPs across the populations suggests that susceptibility factor influences different populations variably. It is pertinent to note that the allele and genotype frequencies analyzed in this study do not essentially cover the complete spectrum of variants at a locus. However, such reports may lead to the future creation of epidemiological and clinical databases.

Genome-wide association studies and genetic-association studies have led to the development of extensive data repositories during the past decade [60]. Identification of critical genes and/or their SNPs involved in the development of early prevention programs and treatments of disease needs multiple assessments of genetic association. However, several bottlenecks like statistical and computational trials and reproducibility factor are required to be tackled before the identification of novel genetic biomarkers for use in gene-disease-association analysis [58],[61],[62].

This study suggests that XRCC1 exon 10 variant allele in Saudi population is significantly different from many populations, globally. The findings may contribute to the population screening of cancer; moreover, the variances in the frequency distribution of the critical DNA repair gene in healthy Saudi population and other racial groups may help in evaluating the disease predisposition and relevance. Additionally, the ascertainment of the susceptibility factors linked with individual susceptibility and predisposition to diseases like cancer may provide clues about the etiology of carcinogenesis in Saudi population. However, future large studies considering a gene–gene and gene–environment interaction are needed to use this polymorphism as a biomarker for the large-scale screening for cancer.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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