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Int J Mol Epidemiol Genet 2012;3(3):228-236

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

Xuemei Zhang, Jie Lin, Xifeng Wu, Zhongning Lin, Baitang Ning, Susan Kadlubar, Fred F Kadlubar

University of Arkansas for Medical Sciences, Little Rock, AR 72205; The University of Texas M.D. Anderson Cancer Center,
Houston, TX; National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR

Received July 13, 2012; accepted August 6, 2012; Epub August 31, 2012; Published September 15, 2012

Abstract: This study sought to determine the role of copy number variants (CNV) combined with other genetic variants in the
Glutathione S-transferases Mu class1 (GSTM1) 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 GSTM1 (OR=0.56; 95%CI=0.39-0.81) but not in those with 1 copy of the gene. GSTM1 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 INS-1543-C-1529-A-1429 in LD block 1, A-1143-A-888 in LD block 2, C-498-G-486-T-471
in LD block 3, C-344-A-343-C-341-C-339 and C-344-A-343-C-341-T-339 in LD block 4. These results suggest that GSTM1 CNV
is a better predictor of bladder cancer susceptibility than measuring presence/absence of GSTM1 and other genetic variants
also can modify bladder cancer risk. (IJMEG1207003).

Keywords: Glutathione-S-transferase M1, Copy number variant, single nucleotide polymorphism, bladder cancer

Address all correspondence to:
Dr. Susan Kadlubar
Division of Medical Genetics
University of Arkansas for Medical Sciences
4301 West Markham Street, #580
Little Rock, AR 72205, USA.
Tel: 501-526-7957; Fax: 501-686-6639
E-mail: SAKadlubar@uams.edu