Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Apr 14;107(5):djv100.
doi: 10.1093/jnci/djv100. Print 2015 May.

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis

Li-Shiun Chen  1 , Rayjean J Hung  1 , Timothy Baker  1 , Amy Horton  1 , Rob Culverhouse  1 , Nancy Saccone  1 , Iona Cheng  1 , Bo Deng  1 , Younghun Han  1 , Helen M Hansen  1 , Janet Horsman  1 , Claire Kim  1 , Sharon Lutz  1 , Albert Rosenberger  1 , Katja K Aben  1 , Angeline S Andrew  1 , Naomi Breslau  1 , Shen-Chih Chang  1 , Aida Karina Dieffenbach  1 , Hendrik Dienemann  1 , Brittni Frederiksen  1 , Jiali Han  1 , Dorothy K Hatsukami  1 , Eric O Johnson  1 , Mala Pande  1 , Margaret R Wrensch  1 , John McLaughlin  1 , Vidar Skaug  1 , Henricus F van der Heijden  1 , Jason Wampfler  1 , Angela Wenzlaff  1 , Penella Woll  1 , Shanbeh Zienolddiny  1 , Heike Bickeböller  1 , Hermann Brenner  1 , Eric J Duell  1 , Aage Haugen  1 , Joachim Heinrich  1 , John E Hokanson  1 , David J Hunter  1 , Lambertus A Kiemeney  1 , Philip Lazarus  1 , Loic Le Marchand  1 , Geoffrey Liu  1 , Jose Mayordomo  1 , Angela Risch  1 , Ann G Schwartz  1 , Dawn Teare  1 , Xifeng Wu  1 , John K Wiencke  1 , Ping Yang  1 , Zuo-Feng Zhang  1 , Margaret R Spitz  1 , Peter Kraft  1 , Christopher I Amos  1 , Laura J Bierut  1
Affiliations
Review

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis

Li-Shiun Chen et al. J Natl Cancer Inst. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Effect of CHRNA5 rs16969968 on delayed smoking cessation among subjects without smoking-related disorders. Smoking-related disorders were lung cancer, chronic obstructive pulmonary disorder, and coronary heart disease. All models adjusted for age, sex, and rs16969968. Random effect models are shown, P heterogeneity = .32 for group A, .027 for group B, and .0058 when all groups combined. * Individual-level data for these marked studies were available and used for the pooled analysis (n = 13 285). All statistical tests were two-sided. CHD = coronary heart disease; COPD = chronic obstructive pulmonary disorder.
Figure 2.
Figure 2.
Effect of CHRNA5 rs16969968 on diagnosis age among smokers with lung cancer. All models adjusted for sex and rs16969968. Random effect model is shown, P heterogeneity = .53. * Individual-level data for all studies are available and used for the pooled analysis (n = 7074). All statistical tests were two-sided.
Figure 3.
Figure 3.
Summary diagram of CHRNA5 rs16969968 genotype, age of smoking cessation, and age of lung cancer diagnosis. * Associations are supported by existing evidence (4–7,19,23). a No longer statistically significant after adjusting for heavy smoking. b Remains statistically significant after adjusting for heavy smoking.
See this image and copyright information in PMC

References

    1. Bierut LJ, Madden PA, Breslau N, et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 2007;16(1):24–35. - PMC - PubMed
    1. Bierut LJ, Stitzel JA, Wang JC, et al. Nicotine Dependence and the a5-a3-b4 Nicotinic Receptor gene cluster: Variants in the Nicotinic Receptors Alter the Risk for Nicotine Dependence. American J Psychiatry. 2008;9(165):1163–1171. - PMC - PubMed
    1. Liu JZ, Tozzi F, Waterworth DM, et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet. 2010;42(5):436–440. - PMC - PubMed
    1. Saccone NL, Culverhouse RC, Schwantes-An TH, et al. Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet. 2010;6(8):1–16. - PMC - PubMed
    1. TAG. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet. 2010;42(5):441–447. - PMC - PubMed

Publication types

Grants and funding