Objective: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. Method: In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. Results: For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Conclusions: Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.
Bibliographical noteFunding Information:
Laura J. Bierut is listed as an inventor on issued U.S. Patent 8,080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Nancy Saccone's spouse is also listed as an inventor on the above issued U.S. Patent 8,080,371. Robert M. Carney or a member of his family owns stock in Pfizer, Inc. Douglas Jorenby has received research support from Pfizer. All other authors declare no potential conflict of interest.
This research was supported by NIH grants P01 CA089392 (LJB) , P30 CA036583 (LJB) , P50 CA84724 (TBB) , and K05 CA139871 (TBB) from the National Cancer Institute , P50 DA19706 (TBB) , K02 DA021237 (LJB) , R01 DA036583 (LJB) , R01 DA025888 (LJB) , K08 DA030398 (LSC) , and R01 DA038076 (LSC) from the National Institute on Drug Abuse , U01 HG004422 (LJB) from the National Human Genome Research Institute , sub-award KL2 RR024994 (LSC) from the National Center for Research Resources , and from The Alvin J. Siteman Cancer Center (SCC) at Washington University School of Medicine (WUSM) and Barnes-Jewish Hospital (BJH) cancer center support grant P30 CA091842 (LJB) . The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health. Genotyping services for the UW-TTURC sample were provided by the Center for Inherited Disease Research (CIDR). Funding support for CIDR was provided by NIH grant U01 HG004438 and NIH contract HHSN268200782096C to The Johns Hopkins University. Assistance with genotype cleaning was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Pfizer conducted the varenicline Trial and supported an Investigator-initiated data use agreement for this manuscript.
© 2015 Elsevier Ireland Ltd.
- Nicotine replacement therapy
- Smoking cessation