Polymorphisms of LIG4 and XRCC4 involved in the NHEJ pathway interact to modify risk of glioma

Although the role of environmental risk factors in the etiology of gliomas remains to be elucidated, accumulative epidemiological evidence suggests that genetic factors, such as variants in genes involved in DNA repair, may also play an important role. LIG4 and XRCC4 are known to form a complex and are functionally linked in the repair of double-stranded DNA breaks. To determine whether LIG4 and XRCC4 polymorphisms are associated with susceptibility to glioma and whether there are interactions between LIG4 and XRCC4, we conducted a case-control study of 771 glioma patients and 752 cancer-free controls, assessed the associations between glioma risk and 20 tagging SNPs, and evaluated their potential gene-gene interactions using the multifactor dimensionality reduction (MDR), interaction dendrogram, and entropy analysis. In the single-locus analysis, only one variant, the LIG4 SNP2 rs3093739:T>C (P-permutation = 0.009) was significantly associated with risk of developing glioma. Haplotype analysis revealed an association of glioma risk with genetic variants in LIG4 block 1 (global P = 0.011), and XRCC4 blocks 2 and 4 (both global P<0.0001). Moreover, the MDR analysis suggested a significant three-locus interaction model involving LIG4 SNP4 rs1805388:C>T, XRCC4 SNP12 rs7734849:A>T, and SNP15 rs1056503:G>T. Further dendrogram and graph analysis indicated a more-than-additive effect among these three loci. These results suggested that these variants may contribute to glioma susceptibility.