Li-Shiun Chen1, Timothy B Baker2, Douglas Jorenby2, Megan Piper2, Nancy Saccone3, Eric Johnson4, Naomi Breslau5, Dorothy Hatsukami6, Robert M Carney7, Laura J Bierut8. 1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, United States; The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, United States. Electronic address: chenli@psychiatry.wustl.edu. 2. Center for Tobacco Research and Intervention, University of Wisconsin, School of Medicine and Public Health, Madison, WI, 53711, United States. 3. Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, United States. 4. Division of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, 27709, United States. 5. Department of Epidemiology, Michigan State University, East Lansing, MI, 48824, United States. 6. Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55455, United States. 7. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, United States. 8. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, United States; The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, United States.
Abstract
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 (X(2)=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.
RCT Entities:
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 CHRNA5rs16969968 and abstinence at end of treatment. RESULTS: For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X(2)=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.
Authors: Li-Shiun Chen; Timothy B Baker; Megan E Piper; Naomi Breslau; Dale S Cannon; Kimberly F Doheny; Stephanie M Gogarten; Eric O Johnson; Nancy L Saccone; Jen C Wang; Robert B Weiss; Alison M Goate; Laura Jean Bierut Journal: Am J Psychiatry Date: 2012-07 Impact factor: 18.112
Authors: Jane E Sarginson; Joel D Killen; Laura C Lazzeroni; Stephen P Fortmann; Heather S Ryan; Alan F Schatzberg; Greer M Murphy Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2011-01-25 Impact factor: 3.568
Authors: Douglas E Jorenby; J Taylor Hays; Nancy A Rigotti; Salomon Azoulay; Eric J Watsky; Kathryn E Williams; Clare B Billing; Jason Gong; Karen R Reeves Journal: JAMA Date: 2006-07-05 Impact factor: 56.272
Authors: Li-Shiun Chen; Timothy B Baker; J Philip Miller; Michael Bray; Nina Smock; Jingling Chen; Faith Stoneking; Robert C Culverhouse; Nancy L Saccone; Christopher I Amos; Robert M Carney; Douglas E Jorenby; Laura J Bierut Journal: Clin Pharmacol Ther Date: 2020-08-04 Impact factor: 6.875
Authors: Robert C Culverhouse; Li-Shiun Chen; Nancy L Saccone; Yinjiao Ma; Megan E Piper; Timothy B Baker; Laura J Bierut Journal: Nicotine Tob Res Date: 2020-02-06 Impact factor: 4.244
Authors: Naji C Salloum; Erica L F Buchalter; Swati Chanani; Gemma Espejo; Mahjabeen S Ismail; Randy O Laine; Maysaa Nageeb; A Benjamin Srivastava; Nicholas Trapp; Ludwig Trillo; Erica Vance; Michael Wenzinger; Sarah M Hartz; Sean P David; Li-Shiun Chen Journal: Pharmacogenomics Date: 2018-06-19 Impact factor: 2.533
Authors: Alex T Ramsey; Li-Shiun Chen; Sarah M Hartz; Nancy L Saccone; Sherri L Fisher; Enola K Proctor; Laura J Bierut Journal: Transl Behav Med Date: 2018-01-29 Impact factor: 3.046