CHRNA5/CHRNA3 Locus Associates with Increased Mortality among Smokers

Abstract

Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2–3.8 and 1.3, 95% CI 1.1–1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0–5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1–1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.

Keywords:

• COPD
• mortality
• single nucleotide polymorphism
• smoking

Acknowledgments

The authors would like to thank Professor Ingileif Jonsdottir and the personnel of deCODE Genetics, Iceland for DNA extraction and genotyping, clinical research nurses Ms. Kerstin Ahlskog, Kirsi Sariola, and Päivi Laakso for their skillful patient recruitment, and Ms. Tuula Lahtinen for monitoring of the project.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Appendix A

Table A1. Risk factors for having >40 pack-years

Table A2. Risk factors for having any type of cancer

Additional information

Funding

This study was supported by the funding of Helsinki University Hospital (HUS EVO), University of Helsinki, TEKES (Salwe research program: Intelligent Monitoring), the Finnish Anti-Tuberculosis Association Foundation, Yrjö Jahnsson Foundation, The Research Foundation of the Pulmonary Diseases, Ida Montin Foundation, Väinö and Laina Kivi Foundation. The ATBC Study was supported by Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN 261201000006C from the U.S. National Cancer Institute.