Journal of the National Cancer Institute Advance Access published online on October 28, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn363
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© The Author 2008. Published by Oxford University Press.
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The CHRNA5-A3 Region on Chromosome 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer
Affiliation of the authors: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Margaret R. Spitz, MD, MPH, Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439 (e-mail: mspitz{at}mdanderson.org).
Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk.
| CONTEXT AND CAVEATS Prior knowledge Recently, genetic variations in a region of chromosome 15 that encompasses a gene implicated in nicotine dependence had been linked to the risk of lung cancer in genome-wide association studies, but data were not definitive as to whether the variants were linked to lung cancer per se or to nicotine dependence. Study design The associations of one of the genetic variants with a number of measures of nicotine dependence were studied using a set of case and control subjects from the initial studies. The risk of lung cancer conferred by the genetic variants was also evaluated in a group of case and control subjects who reported that they had never smoked. Contribution The results of this study suggested that the variant allele was associated with a number of measures of increased nicotine dependence, including higher scores on the Fagerstrom Test of Nicotine Dependence. No association of the genetic variant with lung cancer risk observed in never smokers. Implications The increased risk of lung cancer conferred by the genetic variants might be explained by an increased likelihood of nicotine dependence, although some of the results of this study and a previous study of the variant in subjects who reported that they had never smoked suggests that the variants may also have a direct role in lung carcinogenesis. Limitations The many tests of association performed in the present study raise the possibility that some of the reported associations may be due to chance alone. From the Editors
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Manuscript received May 8, 2008; revised August 15, 2008; accepted September 8, 2008.
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J Natl Cancer Inst 2008 100: 1485.
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