Recent
genome-wide association studies have identified several lung cancer susceptibility
loci. We previously carried out a replication study in male Japanese smokers
that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor
protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5,
2011, pp. 690-696). The current study was performed to
confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C)
and aldehyde dehydrogenase 2 (ALDH2)]
in 1039 male Japanese smokers (573 lung
cancer patients and 466 healthy control
subjects) who were previously enrolled in a study to investigate the low odds
ratio for lung cancer risk associated with functionally impaired and deletion
polymorphisms in cytochrome P450 2A6
(CYP2A6). The
minor allele frequency of rs671 in
ALDH2 (0.304) was significantly higher
in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95%
confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant
association of rs698 in ADH1C with lung
cancer risk was found in this population of male Japanese smokers. For light
smokers categorized according to the 50th percentile Brinkman index value among
the control subjects (620 daily cigarettes × years) and for the CYP2A6*1
wild-type non-carrier sub-population, significantly high odds ratios of 1.98
and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively,
were observed for rs671 in ALDH2.
The present results support the association of ALDH2 loci with
lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light
smokers. CYP2A6 polymorphisms,
including copy number polymorphisms, may lower the risk of heavy tobacco
use-related lung cancer.