The genetics of smoking in individuals with chronic obstructive pulmonary disease

Abstract

Background: 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.

Methods: 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.

Results: For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10- 8) with top SNP rs10023464, P = 1.27 × 10- 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10- 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10- 8). 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.

Conclusion: 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.

Trial registration: The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.

Keywords: Cessation; Cotinine; GWAS; Smoking; eCO.

Conflict of interest statement

Ethics approval and consent to participate

Work undertaken in this manuscript was approved by the University of British Columbia Institutional Review Board, certificate numberH16–01201.

Consent for publication

Not applicable.

Competing interests

Dr. Sin has received research funding from AstraZeneca (AZ), Merck, Boehringer Ingelheim (BI) and Novartis and has received honorarium for speaking engagements from AZ, Novartis, Regeneron and Sanofi-Aventis.

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Figures

Fig. 1

Overall LHS smoking GWAS study design. eCO: exhaled carbon monoxide. CPD: Cigarettes per day. Y1: year 1. eCO was measured in those reporting current smoking

Fig. 2

Manhattan plots of smoking GWASs in Lung Health Study. The plots show the P values (−log10 scale) on the Y axes and the SNP positions across 22 autosomal chromosomes on the X axes. The horizontal red line represents the genome-wide cut-off of 5 × 10− 08

Fig. 3

Region plots of the smoking associated loci. The Y axis represent the P values in the (−log10 scale) and the X axis is the genomic position. Gene names and their corresponding coordinates are shown below. The sentinel SNP is shown as a purple diamond and the color coding of SNPs reflects the degree of linkage disequilibrium (LD) with the sentinel SNP using 1000G reference