Frequency of XRCC1 exon 10 G>A gene polymorphism in the Saudi Arabian Population: Inter-individual study from different ethnic groups

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The inability of the host system to repair such defective or destructive DNA may lead to carcinogenesis in the individuals.The person to person variations in their susceptibilities to cancer can be attributed to genetic alterations which affect DNA repair capabilities (de Jong et al. 2002).
Single-nucleotide polymorphisms (SNPs) are the DNA base variants present in the human population.They are present in at least 1% population (Collins et al. 1997) and are usually less penetrant, but their study in cancer is very important (Perera et al. 2000).
The inherent difference in the capacity of individuals to repair DNA lesion is induced by endogenous and exogenous carcinogens.
These genetic polymorphisms and adverse genotypes have been suggested to reduce DNA repair capacity (DRC) and modify individual susceptibility for cancer than general population (Wu et al. 2004).Hence, the results obtained from the studies done on inter individual variations in different ethnic groups could possibly give further insight to discover candidate susceptibility alleles in the etiology of carcinogenesis.
The X-ray cross-complementing gene 1 (XRCC1) is mapped on chromosome 9q13.2.It consists of 17 exons and encodes a protein of 633 amino acids.XRCC1 plays an important role in multi-step base excision repair (BER) pathway to remove the 'nonbulky' base adducts produced by methylation, oxidation, reduction or fragmentation of bases by ionizing radiation or oxidative damage (Yu et al. 1999).It is a scaffolding protein consisting of three DNA repair enzymes: DNA ligase III, DNA polymerase b and poly(adenosine diphosphate (ADP)ribose) polymerase (PARP) involved in excision and recombinational repair pathways (Petermann et al. 2006).The significance of XRCC1 came into light with null mutant mice experiment.The null mutant mice with error in XRCC1 gene demonstrated embryonic development arrest (Tebbs et al. 1999).Different polymorphisms have been reported in XRCC1 gene, but the extensively studied is at codon 399 in exon 10 (Arg to Gln).It is located in the BRCT-I interaction domain of XRCC1 gene within a poly (ADPribose) polymerase binding region (Shen et al. 1998).In the year 1999, a team of scientists linked the above mentioned polymorphism to change in DNA repair capacity of the said gene (Lunn et al. 1999).These changes in the conserved sites of the protein were believed to amend base excision repair capacity.This negative amendment was found to downgrade the ability of human beings to fight adverse health conditions including cancer (Hung et al. 2005).The current study deals to investigate the frequency distribution of XRCC1 exon 10 Arg399Gln, G23591A, rs25487 polymorphism in normal healthy individuals from Saudi Arabia, wherein different epidemiologic studies performed globally were considered for comparative analysis.

MATERIALS AND METHODS Prevalence of gene variants:
PUBMED (Medline) webdatabase was searched for pertinent articles using ''XRCC1'' and ''polymorphism''.It was restricted to human subjects but covered all the languages.The genotype frequencies for the control population were considered for casecontrol studies.Those studies focusing only on allele frequencies and no genotype frequencies were excluded straightaway.In case of more than one hits for the same study population, the most recent publication was included.The number of publications identified and considered for the current study were 22 which were based on the prevalence of XRCC1 exon 10 (G>A) polymorphism, and were later used for the comparison with Saudi Arabian population .

Statistical analysis:
Pearson's χ2 test was performed for the comparative analysis of the genotype and allelic frequencies of different populations by using SPSS (version 21) statistical software program.Court-Lab (web-based software program) was used to examine Hardy-Weinberg equilibrium.p-value 0.05 was maintained for statistically significant outcomes.

RESULTS
The distribution of XRCC1 (exon 10, G>A) genotype frequencies in Saudi Arabian population has been given in Table 1.The genotype distributions were in accordance with Hardy-Weinberg equilibrium (HWE).The frequency distribution of three genotypes and alleles of this polymorphism of different populations with reference to our population were compared using χ2 tests (Table 2).

DISCUSSION
It is well known these days on the basis of accumulating evidences that genetic variations influence the risk of environmental carcinogenesis and genetic susceptibility plays an important role in the development of human cancer.The new studies on genetic association of cancer risks have assisted in identifying the effects of SNPs as candidate genes.Among the cancer repair genes are most studied as they responsible for maintaining genome integrity.The analyzed studies suggest that inherited mutations in DNA repair genes exposes the individuals to exceptionally high risk for the development of cancer (Au et al. 2004).Due to the well-known differences in the distribution of DNA repair gene polymorphisms among several worldwide ethnic groups, the data from 'normal healthy' populations are of special interest.It can be used to establish the relevance, which further could be used for the evaluation of the investigated genetic markers in the susceptibility, manifestation, prognosis or treatment of deadly diseases.Many reports published on DNA repair gene polymorphisms have already proved their potential in disease related clinical roles in determining both inter-individual and inter-ethnic differences in carcinogenesis (Kittles et al. 2003).Saudi Arabian population is considered to be one of the most diverse population all over the world, and hence can be used to study the genetic variation vis a vis other populations.Therefore, there is a potential that it may have future propositions for the preventions as well as early intervention strategies.The current article compares the frequency distribution of XRCC1 exon 10 G>A genetic variant in Saudi Arabian population from other populations of the world based on the published articles.
The repair of damaged DNA is foremost parameter to protect the cells against cancer (Friedberg 2003).The XRCC1 gene studied in this paper plays an important role in repairing both single-strand break and the base excision (Cappelli et al. 1997).The cells lacking XRCC1 gene are genetically unstable and sensitive to DNA damaging agents such as Ionizing radiation, alkylating agents, ultra-violet light and hydrogen peroxide (Kubota et al. 1996).It is also known that variants of XRCC1 gene contributes to ionizing radiation susceptibility, for which the prolonged cell cycle G delay is considered as one of the indicators (Hu et al. 2001).
In the present study, the interesting finding is the significance of mutant allele (A).The frequency of this variant allele (A) of Exon 10 in Saudi Arabia population was found to be 22.3%.It was significantly different from many other countries of the world.It was found to be lower from Thailand, Iran, Japan, North India, Germany, Poland, France, Norway, USA, Pakistan etc., whereas it was similar to Korea, china and Taiwan, respectively.The differences in allelic frequency in these studies can be attributed to several reasons such as ethnic variation, heterogeneity of study populations and different sample sizes.Earlier reports have demonstrated the distinct patterns of DNA repair genes in comparison with different populations of other countries (Mandal et al. 2010;Areeshi et al. 2013).The differences in the prevalence of DNA repair polymorphisms across different populations indicate that susceptibility factor in one population may not hold true for another.These types of studies may be helpful in forming the basis for future establishment of epidemiological and clinical databases.It should also be emphasized that for most instances, the allele and genotype frequencies presented here do not always consider the complete spectrum of variants at a locus.The current study concludes that XRCC1 exon10 allelic variant in Saudi Arabian population is significantly different from other populations.This information may be used as basis that can act as a contributing factor in the screening of cancer.The differences in the distribution of these DNA repair genes in healthy Saudi Arabian population and other ethnic groups can be used in making a profile that may help in assessing the disease predisposition and prevalence.The identification of the susceptibility factors associated with individual predisposition to cancer could possibly give further insight in to the etiology of carcinogenesis.Also, future large studies and biological characterization is warranted to use this polymorphism as a biomarker for the screening purpose for cancer.

Table 1 .
Observed and expected genotypic frequencies of XRCC1 Exon 10 G>A polymorphism in the control group.

Table 2 .
Genotype and allele frequency distribution of XRCC1 Exon 10 G>A gene variant in various populations and p-values in comparison to Saudi Arabian population