Chromosome 15q25 (CHRNA3-CHRNA5) Variation Impacts Indirectly on Lung Cancer Risk

Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10−10) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10−6) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10−5 and P = 5.65×10−3). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk.

已有研究证实，15q25染色体区域CHRNA5-CHRNA3基因座（15q25 CHRNA5-CHRNA3 locus）的遗传变异可影响肺癌易感性，但关于此类变异究竟是直接对肺癌风险产生致癌效应，还是通过吸烟行为间接发挥作用，目前仍存在争议。本研究依托肺癌遗传易感性研究（Genetic Lung Cancer Predisposition Study, GELCAPS）的队列数据，纳入4343例肺癌患者与1479例对照人群，对15q25区域的肺癌风险变异rs12914385和rs8042374与吸烟行为、肺癌风险的关联展开了详细分析。结果显示，rs12914385与rs8042374均与肺癌风险存在显著关联：二者的比值比（odds ratio, OR）分别为1.44（95%置信区间（confidence interval, CI）：1.29~1.62，P=3.69×10⁻¹⁰）与1.35（95%CI：1.18~1.55，P=9.99×10⁻⁶）。rs12914385与rs8042374位点上的每一份风险等位基因，分别与每日吸烟量（cigarettes per day, CPD）增加1.0支和0.9支显著相关（P=5.18×10⁻⁵、P=5.65×10⁻³）。上述由遗传因素决定的吸烟行为小幅差异，足以解释15q25区域变异与肺癌风险的关联。为进一步验证15q25区域变异对肺癌风险的间接效应，本研究将肺癌风险分析限定于从不吸烟者群体，并对已发表的从不吸烟者肺癌风险相关研究开展了荟萃分析（meta-analysis）。本研究通过PubMed数据库检索已发表的英文文献，检索关键词限定为：肺癌、风险、全基因组关联（genome-wide association）、候选基因，筛选针对从不吸烟者的相关研究。本研究联合此前5项已发表的研究，最终纳入2405例从不吸烟者肺癌患者与7622例对照人群的研究数据。合并分析结果显示，15q25区域变异与肺癌风险无显著关联（OR=1.09，95%CI：0.94~1.28）。本研究证实了15q25区域变异与吸烟行为的关联，且支持基因型通过间接途径影响肺癌风险的结论。