JNCI：遗传变异对肺癌风险的贡献不容忽视

据4月25日发表在National Cancer Institute杂志上的一项研究证实：rs1051730-rs16969968基因型和烟草暴露之间的关系引发了患肺癌风险增高。

rs1051730-rs16969968基因型与吸烟、肺癌以及其他与吸烟有关的后果有一定联系。此前的研究一般依靠吸烟者对吸烟行为的自我报告，这可能低估了并掩盖了吸烟对肺癌和其他健康结果这些多态性疾病的贡献。

布里斯托尔大学实验心理学博士Marcus R. Munafò和他的同事从六个独立的研究中考察自我报告的卷烟消费量和血浆或血清中可铁宁水平之间的关联，确定了rs1051730-rs16969968基因型与肺癌风险之间的联系。此外，研究者使用已经发表的数据分析了可替宁水平与肺癌风险之间的联系，探讨了基因型与肺癌风险之间的关系。

研究人员通过测量可替宁水平发现rs1051730-rs16969968基因型与烟草暴露强烈有关。这些数据支持rs1051730-rs16969968基因型与肺癌风险的关系主要是有烟草暴露引起的。然而研究人员指出，这项研究还存在某些限制如数据来自不同研究的不同人群等。

doi:10.1093/jnci/djs191
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Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure

Marcus R. Munafò, Maria N. Timofeeva, Richard W. Morris, David Prieto-Merino, Naveed Sattar, Paul Brennan, et al.

Background Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.

Methods We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.

Results Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10⁻⁶) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10⁻¹¹). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).

Conclusions Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.