Carcinogenesis Advance Access published online on March 26, 2007
Carcinogenesis, doi:10.1093/carcin/bgm073
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Tagging SNPs in Nonhomologous End-Joining Pathway Genes and Risk of Glioma
1 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences
2 Neurosurgery Department of Huashan Hospital, Fudan University, Shanghai, China
3 Department of Social Medicine, University of Bristol, Bristol, UK
4 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
5 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
* To whom correspondence should be addressed at: Daru Lu, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 220 Handan Rd., Shanghai 200433, China. Email: drlu{at}fudan.edu.cn; or Fengping Huang, Neurosurgery Department of Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Rd., Shanghai 200040, China. Email: huangfengping_neuro{at}hotmail.com
Ionizing radiation is known to cause DNA damage, including single-strand and double-strand DNA breaks (DSBs), and the unrepair of DNA damage, particularly DSBs, may cause chromosome aberrations. Although the etiology of gliomas remains unclear, exposure to ionizing radiation has been identified as the only established risk factor. We hypothesized that polymorphisms of candidate genes involved in the DSBs repair pathway may contribute to susceptibility to glioma. We used a haplotype-based approach to investigate the role of 22 tagging single nucleotide polymorphisms (tSNPs) of XRCC5, XRCC6 and XRCC7 in 771 glioma patients and 752 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, haplotypes were inferred by the HAPLO.STAT program, and gene-gene interactions were evaluated by the multifactor dimensionality reduction (MDR) method. We found that, in the single locus analysis, glioma risk was statistically significantly associated with three XRCC5 tSNPs (SNP1 rs828704, SNP6 rs3770502 and SNP7 rs9288516, P = 0.005, 0.042 and 0.003, respectively), one XRCC6 tSNP (SNP4 rs6519265, P = 0.044), but none of XPCC7 tSNPs. Haplotype-based association analysis revealed that gliomas risk was statistically significantly associated with one protective XRCC5 haplotype "CAGTT", accounting for a 40% reduction (OR=0.60, 95% CI = 0.43 - 0.85) in glioma risk, and some positive gene-gene interactions were also evident. In conclusion, genetic variants of the genes involved in the DSB repair pathway may play a role in the etiology of glioma.
# YH Liu and HS Zhang contributed equally to this work.
Received January 31, 2007; revised March 15, 2007; accepted March 21, 2007.
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