The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
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DOI：
10.1093/jnci/djn363
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发表时间：
2008-11-05
期刊：
影响因子：
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通讯作者：
Wu, Xifeng
中科院分区：
文献类型：
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作者：
Spitz, Margaret R;Amos, Christopher I;Wu, Xifeng
在最近发表的三项独立进行的全基因组关联研究中，染色体 15q24-25.1 烟碱乙酰胆碱受体基因簇的常见变异与肺癌风险相关，但对于这些变异对吸烟倾向与直接致癌作用的相对影响尚未达成共识。为了进一步探讨我们的假设，即这些变异确实与癌症病因和尼古丁依赖相关，我们对这些假定的风险基因型与吸烟表型、以及一生从不吸烟者和其他与吸烟相关的癌症的关联进行了更详细的分析。我们证明了这些变异与尼古丁依赖以及肺癌表型（包括肺癌发病年龄较早）之间存在统计学上显着的关联。这些变异与吸烟暴露程度较低的阶层以及具有肺癌或吸烟相关癌症家族史的个体的较高肺癌风险相关。相比之下，我们没有发现任何证据表明这些变异与 547 名终生不吸烟的肺癌病例受试者或其他与吸烟相关的癌症（膀胱癌和肾癌）的风险升高相关。因此，我们得出结论，这些变异不仅与吸烟行为有关，而且更直接地与肺癌风险有关。
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.