Abstract
PARP-1 gene plays an essential part in base excision repair pathway and its functional variations result in several types of cancer. In this study we have explored the effect of genetic variations in PARP-1 gene in brain tumorigenesis. This case control study comprised of 500 brain tumor cases along with 500 healthy controls. Three polymorphisms of PARP-1 gene, rs1136410 (Val762Ala), rs1805404 (Asp81Asp) and rs1805414 (Ala284Ala) were analyzed using AS-PCR method followed by DNA sequencing. Joint effect model, haplotype analysis and linkage disequilibrium of these polymorphisms was assessed using Haploview 4.2. In rs1136410 (Val762Ala) heterozygous mutant genotype (CT) was observed notably lower (OR: 0.44., 95% CI: 0.33–0.57., p<0.0001) in brain tumor patients compared to controls and ~2 fold increased frequency of homozygous mutant genotype (CC) was observed in brain tumor patients versus controls (OR: 1.51., 95%CI: 1.16–1.96, p = 0.001). In rs1805414 (Ala284Ala), frequency of heterozygous mutant genotype (CT) was observed lower (OR: 0.77., 95% CI: 0.60–0.99., p = 0.05) in patients versus controls. In rs1805404 (Asp81Asp), heterozygous mutant genotyping (CT) was observed lower in brain tumor patients compared with the healthy controls (OR: 0.63., 95% CI: 0.48–0.83., p = 0.001). However, homozygous mutant genotype (TT) was observed increased in patients compared to controls (OR: 1.41., 95% CI:1.07–1.85., p = 0.01). We assessed the fact that in combination the PARP-1 gene SNPs, rs1136410 (Val762Ala), rs1805414 (Ala284Ala) and rs1805404 (Asp81Asp) may increase the brain pathogenesis at least in Pakistani population.
Highlights
In case of rs1136410 (Val762Ala), heterozygous mutant genotype (CT) frequency was linked with 56% decrease in brain tumor risk (OR = 0.44, 95% confidence interval (CI): 0.33–0.57; p
~2folds increase in brain tumor risk was found associated with homozygous mutant genotype (CC) (OR = 1.51, 95% CI: 1.16–1.96; p
In rs1805404 (Asp81Asp), heterozygous mutant genotype (CT) frequency was found associated with 37% decrease in brain tumor risk (OR = 0.63, 95% CI: 0.48–0.83; p
Summary
Genetic susceptibility might play a pivotal role in modifying the brain tumor risk [4] To maintain this genetic susceptibility, different DNA repair pathways perform their functions. Rs1805404 (Asp81Asp) in exon 2 at position 81 lies within zinc finger domain These SNPs are associated with the risk of Alzheimer’s disease [8], glioblastoma [9], breast cancer [10] and colorectal cancer [11]. Another SNP of PARP-1 gene, rs1136410 leads to change of valine to alanine at codon 762 of catalytic domain. The frequency of genotypes of selected PARP1 polymorphisms was correlated with different types and grades of the brain tumor in order to further illuminate the role of these polymorphism in brain tumorigenesis
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