Human Molecular Genetics Advance Access originally published online on May 10, 2006
Human Molecular Genetics 2006 15(12):1963-1971; doi:10.1093/hmg/ddl119
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Caspase 9 promoter polymorphisms and risk of primary lung cancer
1Cancer Research Institute and 2Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Dong-In 2Ga 101, Daegu, 700-412, Republic of Korea, 3Department of Biochemistry and 4Department of Preventive Medicine, School of Medicine, Kyungpook National University, Dong-In 2Ga 101, Daegu, 700-422, Republic of Korea and 5Department of Internal Medicine, Kyungpook National University Hospital, Samduk 2Ga 50, Daegu, 700-412, Republic of Korea
* To whom correspondence should be addressed. Tel: +82 534205536; Fax: +82 534262046; Email: jaeyong{at}kyungpook.ac.kr
Received March 7, 2006; Accepted April 28, 2006
Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [–1263A>G, –905T>G, –712C>T and –293_–275delCGTGAGGTCAGTGCGGGGA (–293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The –1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the –1263 AA genotype or combined –1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42–0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46–0.97, P=0.01, respectively]. For the –712C>T polymorphism, individuals with at least one –712T allele were at a significantly increased risk of lung cancer compared with those harboring the –712 CC genotype (adjusted OR=1.42, 95% CI=1.06–1.89, P=0.02). Consistent with the results of genotype analyses, the –1263G/–712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47–0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45–0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17–0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; Ptrend<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the –1263G/–712T and –1263A/–712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.
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