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

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.

SUBMITTER: Chen LS

PROVIDER: S-EPMC4822525 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Chen Li-Shiun LS Hung Rayjean J RJ Baker Timothy T Horton Amy A Culverhouse Rob R Saccone Nancy N Cheng Iona I Deng Bo B Han Younghun Y Hansen Helen M HM Horsman Janet J Kim Claire C Lutz Sharon S Rosenberger Albert A Aben Katja K KK Andrew Angeline S AS Breslau Naomi N Chang Shen-Chih SC Dieffenbach Aida Karina AK Dienemann Hendrik H Frederiksen Brittni B Han Jiali J Hatsukami Dorothy K DK Johnson Eric O EO Pande Mala M Wrensch Margaret R MR McLaughlin John J Skaug Vidar V van der Heijden Henricus F HF Wampfler Jason J Wenzlaff Angela A Woll Penella P Zienolddiny Shanbeh S Bickeböller Heike H Brenner Hermann H Duell Eric J EJ Haugen Aage A Heinrich Joachim J Hokanson John E JE Hunter David J DJ Kiemeney Lambertus A LA Lazarus Philip P Le Marchand Loic L Liu Geoffrey G Mayordomo Jose J Risch Angela A Schwartz Ann G AG Teare Dawn D Wu Xifeng X Wiencke John K JK Yang Ping P Zhang Zuo-Feng ZF Spitz Margaret R MR Kraft Peter P Amos Christopher I CI Bierut Laura J LJ

Journal of the National Cancer Institute 20150414 5

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 25873736

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Project description:IntroductionSmoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design.Aims and methodsThis study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses' Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years.ResultsWomen with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096].ConclusionsSome SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity.ImplicationsThe results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management.

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

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

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