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Original research
Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers
  1. Raewyn J Hopkins1,
  2. Fenghai Duan2,
  3. Greg D Gamble1,
  4. Caroline Chiles3,
  5. Alana Cavadino1,
  6. Paul Billings4,
  7. Denise Aberle5,
  8. Robert P Young1
  1. 1The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand
  2. 2Department of Biostatistics and Centre for Statistical Science, Brown University, Providence, Rhode Island, USA
  3. 3Department of Radiology, Wake Forest Baptist Medical Comprehensive Cancer Center, Winston-Salem, North Carolina, USA
  4. 4Natera Inc, Berkeley, California, USA
  5. 5Department of Radiological Sciences, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
  1. Correspondence to Dr Robert P Young, The University of Auckland Faculty of Medical and Health Sciences, Auckland 1344, New Zealand; roberty{at}


Importance While cholinergic receptor nicotinic alpha 5 (CHRNA5) variants have been linked to lung cancer, chronic obstructive pulmonary disease (COPD) and smoking addiction in case–controls studies, their corelationship is not well understood and requires retesting in a cohort study.

Objective To re-examine the association between the CHRNA5 variant (rs16969968 AA genotype) and the development of lung cancer, relative to its association with COPD and smoking.

Methods In 9270 Non-Hispanic white subjects from the National Lung Screening Trial, a substudy of high-risk smokers were followed for an average of 6.4 years. We compared CHRNA5 genotype according to baseline smoking exposure, lung function and COPD status. We also compared the lung cancer incidence rate, and used multiple logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA5 variant in smoking exposure, COPD and lung cancer.

Results As previously reported, we found the AA high-risk genotype was associated with lower lung function (p=0.005), greater smoking intensity (p<0.001), the presence of COPD (OR 1.28 (95% CI 1.10 to 1.49) p=0.0015) and the development of lung cancer (HR 1.41, (95% CI 1.03 to 1.93) p=0.03). In a mediation analyses, the AA genotype was independently associated with smoking intensity (OR 1.42 (95% CI 1.25 to 1.60, p<0.0001), COPD (OR 1.25, (95% CI 1.66 to 2.53), p=0.0015) and developing lung cancer (OR 1.37, (95% CI 1.03 to 1.82) p=0.03).

Conclusion In this large-prospective study, we found the CHRNA5 rs 16 969 968 AA genotype to be independently associated with smoking exposure, COPD and lung cancer (triple whammy effect).

  • lung cancer
  • COPD epidemiology
  • tobacco and the lung

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  • Contributors Author contribution: RJH, FD, CC, PB, DA and RPY contributed to the conception and design; acquisition, analysis and interpretation; drafting and review for important intellectual content and final approval of the manuscript. GDG and AC contributed to biostatistical analysis and final approval.

  • Funding This study was funded by a grant from Johnson and Johnson and grants U01-CA-80098 and U01-CA-79778 to the American College of Radiology Imaging Network (ACRIN).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information. All clinical data is deidentified. The genetic data are reported in the manuscript.

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