Association and multiple interaction analysis among five XRCC1 polymorphic variants in modulating lung cancer risk in North Indian population

Abstract

XRCC1 is a scaffold protein that provides for interaction of DNA polymerase, DNA ligase and damaged DNA.Genotyping was done for the five non-synonymous and synonymous variants of XRCC1 i.e. XRCC1, Arg194Trp, Pro206Pro, Arg280His, Arg399Gln, Gln632Gln. Logistic regression analysis was used to analyze the association of XRCC1 with lung cancer, followed by data mining analysis which included both Multi-dimensionality reduction (MDR) and Classification and Regression tree (CART) analysis so as to find possible interaction between SNPs on XRCC1 gene.Statistical analysis revealed XRCC1 Gln632Gln (OR=2.67, p=<0.001) depicted an overall high risk towards lung cancer. Histological subdivision revealed carriers of mutant genotype in case of XRCC1 Arg399Gln imposed a protective effect towards SQCC subtype. Likewise, mutant genotype in XRCC1 Pro206Pro implied a protective effect for SCLC subtype (OR=0.29, p=0.0017) on the contrary XRCC1 Gln632Gln showed a high risk in SQCC diseased group (OR=4.16, p=<0.0001).Combination of XRCC1 Gln632Gln with other SNPs revealed XRCC1 Gln632Gln with Arg194Trp (OR=2.10, p=0.03) and Pro206Pro (OR=5.6, p<0.0004) increased an overall risk towards lung cancer. Haplotype analysis illustrated haplotype block 11 (CGAGG) carrying minor allele for XRCC1 206 was associated with the highest risk towards lung cancer on the contrary block 4 (CAGAG) carrying mutant allele for XRCC1 399 significantly decreased the risk. Multi-dimensionality reduction (MDR) results showed the three factor model comprising XRCC1 206, 632, 280 as the best model (CVC=10, prediction error=0.34). Further Classification and Regression tree (CART) analysis revealed terminal node 1 carrying mutant of XRCC1 632 and wild type of XRCC1 280 represented the highest risk group.Our results demonstrated high order interaction between SNPs of XRCC1 gene. This study depicted a positive association of XRCC1 Gln632Gln towards lung cancer, however XRCC1 Arg399Gln, Arg194Trp showed an overall no effect or protective effect.