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CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis
Li-Shiun Chen1, Rayjean J Hung1, Timothy Baker1
1Department of Psychiatry, Washington University School of Medicine, St. Louis, MO (LSC, AHo, LJB); The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO (LSC, LJB); Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada (RJH, JM); Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI (TB); Department of Medicine, Washington University School of Medicine, St. Louis, MO (RC); Department of Genetics, Washington University School of Medicine, St. Louis, MO (NS); Cancer Prevention Institute of California, Fremont, CA (IC); Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN (BD, JW, PY); Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH (YH, CIA); Department of Neurological Surgery, University of California San Francisco, San Francisco, CA (HMH, MRW, JKW); Department of Oncology, University of Sheffield, Sheffield, UK (JHo, PW); Department of Epidemiology, UCLA Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA (CK, ZFZ); Department of Biostatistics & Informatics, University of Colorado Anschutz Medical Campus, Denver, CO (SL); Department of Genetic Epidemiology, University of Goettingen Medical School, Goettingen, Germany (AR, HBi); Comprehensive Cancer Centre, the Netherlands, Utrecht, Netherland & Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands (KKA); Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (ASA); Department of Epidemiology, Michigan State University, East Lansing, MI (NB); Division of Clinical Epidemiology and Aging Research German Cancer Research Center, German Cancer research Center, Heidelberg, Germany (AKD, HBr); German Cancer Consortium, Heidelberg, Germany (AKD, HBr); Department of Thoracic Surgery, Thoraxklinik at University Hospital
Background:
Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.
Methods:
Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided.
Results:
The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)).
Conclusion:
These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.
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