Association between GSTM1 copy number, promoter variants and susceptibility to urinary bladder cancer

摘要

This study sought to determine the role of copy number variants (CNV) combined with other genetic variants in the Glutathione emS/em-transferases Mu class1 (emGSTM1/em) promoter in the development of urinary bladder cancer. TaqMan real-time PCR and direct sequencing were used to determine genetic variants. Haploblocks and haplotype were constructed and estimated by Haploview and Phase, respectively. Logistic regression revealed a significantly decreased bladder cancer risk in subjects with at least 2 copies of emGSTM1/em (OR=0.56; 95%CI=0.39-0.81) but not in those with 1 copy of the gene. emGSTM1/em promoter screening revealed an insertion variant (-1543TTCT) and 14 single nucleotide polymorphisms (SNPs) (-1529C>G, -1490A>G, -1143A>G, -888A>T, -498G>C, -486C>G, -471C>T, -426G>A, -344C>T, -343A>T, -341C>T, -339C>T, -304G>A, and -164C>T). Four haploblocks were evident by Haploview. There was no significant association between any single SNP/haplotype and bladder cancer risk. However, when stratified by copy number, the two copy carriers with the -1543 insertion had decreased bladder cancer risk (OR, 0.58; 95%CI, 0.32-0.10) and similar results were found in two copy carriers with -888 A, -486G, - 344 C, -343 A, -341 C allele and haplotype INSsub-1543/sub-Csub-1529/sub-Asub-1429/sub in LD block 1, Asub-1143/sub-Asub-888/sub in LD block 2, Csub-498/sub-Gsub-486/sub-Tsub-471/sub in LD block 3, Csub-344/sub-Asub-343/sub-Csub-341/sub-Csub-339/sub and Csub-344/sub-Asub-343/sub-Csub-341/sub-Tsub-339/sub in LD block 4. These results suggest that emGSTM1/em CNV is a better predictor of bladder cancer susceptibility than measuring presence/absence of emGSTM1/em and other genetic variants also can modify bladder cancer risk.