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Carcinogenesis Advance Access published online on November 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn257
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Contribution of Nicotine Acetylcholine Receptor Polymorphisms to Lung Cancer Risk in a Smoking -independent Manner in the Japanese

Kouya Shiraishi1, Takashi Kohno1, Hideo Kunitoh2, Shun-ichi Watanabe3, Koichi Goto4, Yutaka Nishiwaki4, Yoko Shimada1, Hiroshi Hirose5, Ikuo Saito5, Aya Kuchiba6, Seiichro Yamamoto7 and Jun Yokota1,8

1 Biology Division, National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan
2 Thoracic Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan
3 Thoracic Surgery Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan
4 Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan
5 Health Center, Keio University School of Medicine, Tokyo, Japan
6 Genetics Division, National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan
7 Cancer Information Services and Surveillance Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan

8 To whom correspondence should be addressed. E-mail: jyokota{at}ncc.go.jp.

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1,250 cases (562 adenocarcinoma, 391 squamous cell carcinoma, and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5 – 3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without, however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.

Key Words: polymorphism • nicotine acetylcholine receptor • lung cancer • smoking

Received August 20, 2008; revised October 14, 2008; accepted November 9, 2008.


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