The University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Respir Res. 2018 Apr 10;19(1):59. doi: 10.1186/s12931-018-0762-7.
Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD.
The LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components.
For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10) with top SNP rs10023464, P = 1.27 × 10. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD.
The study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies.
The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.
吸烟是导致慢性阻塞性肺疾病（COPD）的主要可改变环境风险因素，影响着 3 亿人，是全球第三大死亡原因。大多数关于吸烟的遗传研究都依赖于自我报告的吸烟状况，这种状况容易受到报告和回忆偏差的影响。利用来自肺健康研究（LHS）的数据，我们试图确定与患有轻度至中度 COPD 的个体的定量吸烟和戒烟相关的遗传变异。
LHS 是一项针对轻度至中度 COPD 受试者的纵向多中心研究，这些受试者在招募时均为吸烟者。我们对唾液可替宁（n=4024）、呼出一氧化碳（eCO）（n=2854）、每日吸烟量（CPD）（n=2706）和 5 年随访时的戒烟情况（n=717 名戒烟者和 2175 名吸烟者）进行了全基因组关联研究（GWAS）。GWAS 分析调整了年龄、性别和遗传主要成分。
对于可替宁水平，UGT2B10 基因附近的 SNPs 达到了全基因组显著性水平（即 P<5×10），其中 top SNP rs10023464，P=1.27×10。对于 eCO 水平，确定了一个位于 CHRNA3 基因的显著 SNP（rs12914385，P=2.38×10）。一个映射到 KCNMA1 基因的边界区域与戒烟相关（rs207675，P=5.95×10）。在所确定的基因座中，只有 CHRNA3/5 基因座与肺功能表现出显著相关性，但仅在重度吸烟者中如此。没有任何区域达到 CPD 的全基因组显著性水平。
该研究表明，使用 eCO 和/或唾液可替宁等客观的吸烟测量方法可以更精确地捕捉到吸烟行为多个方面的遗传贡献。KCNMA1 基因与戒烟的关联可能代表了一个潜在的治疗靶点，值得进一步研究。
肺健康研究临床Trials.gov 标识符：NCT00000568。注册日期：1999 年 10 月 28 日。
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