TY - JOUR
T1 - Genetic Variant in CHRNA5 and Response to Varenicline and Combination Nicotine Replacement in a Randomized Placebo-Controlled Trial
AU - Chen, Li Shiun
AU - Baker, Timothy B.
AU - Miller, J. Philip
AU - Bray, Michael
AU - Smock, Nina
AU - Chen, Jingling
AU - Stoneking, Faith
AU - Culverhouse, Robert C.
AU - Saccone, Nancy L.
AU - Amos, Christopher I.
AU - Carney, Robert M.
AU - Jorenby, Douglas E.
AU - Bierut, Laura J.
N1 - Funding Information:
L.‐S.C. was supported by the National Institute on Drug Abuse grant R01 DA038076, Siteman Cancer Center and NCI Cancer Center Support Grant P30 CA091842. T.B.B.’s involvement was supported in part by R01 HL109031. L.J.B. was supported by National Center for Advancing Translation Sciences grant UL1TR002345. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. L.‐S.C. obtained free supply of study medication (varenicline and placebo) for this trial from Pfizer with an investigator‐initiated research agreement (IIR). This free Pfizer product constitutes the support for this study. The funding source had no role in the study design, collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the paper for publication. The corresponding author had full access to the data in the trial and had final responsibility for the decision to submit for publication.
Funding Information:
L.-S.C. was supported by the National Institute on Drug Abuse grant R01 DA038076, Siteman Cancer Center and NCI Cancer Center Support Grant P30 CA091842. T.B.B.?s involvement was supported in part by R01 HL109031. C.I.A. is a research scholar of the Cancer Prevention Research Institute of Texas and partially supported by RR170048. L.-S.C., L.J.B. and C.I.A. are partially supported by U19CA203654. L.J.B. was supported by National Center for Advancing Translation Sciences grant UL1TR002345. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. L.-S.C. obtained free supply of study medication (varenicline and placebo) for this trial from Pfizer with an investigator-initiated research agreement (IIR). This free Pfizer product constitutes the support for this study. The funding source had no role in the study design, collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the paper for publication. The corresponding author had full access to the data in the trial and had final responsibility for the decision to submit for publication. [Correction added on 25 August 2020, after first online publication: The following funding details were included, ?C.I.A. is a research scholar of the Cancer Prevention Research Institute of Texas and partially supported by RR170048. L.-S.C., L.J.B. and C.I.A. are partially supported by U19CA203654?.] The authors thank Mario Castro, Brian Gage, Eric Lenze, and Sharon Cresci for their contributions to data and safety monitoring. The authors also thank the staff and students at Washington University Health and Behavior Research Center for their help with this research.
Publisher Copyright:
© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics
PY - 2020/12
Y1 - 2020/12
N2 - It is unclear if genetic variants affect smoking cessation treatment response. This study tested whether variants in the cholinergic receptor nicotinic alpha 5 subunit (CHRNA5) predict response to smoking cessation medication by directly comparing the two most effective smoking cessation pharmacotherapies. In this genotype-stratified randomized, double-blind, placebo-controlled clinical trial (May 2015–August 2019 in St Louis, Missouri), smokers were randomized by genotype in blocks of six (1:1:1 ratio) to three conditions: 12 weeks of placebo (n = 273), combination nicotine patch and lozenge (combination nicotine replacement therapy, cNRT, n = 275), or varenicline (n = 274). All participants received counseling and were followed for 12 months. The primary end point was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT, week 12). Trial registration and eligibility criteria are on clinicaltrials.gov (https://clinicaltrials.gov/) (NCT02351167). We conducted the genetic analyses separately for 516 European ancestry (EA) smokers and 306 non-EA smokers (including 270 African American smokers). In African American smokers, there was a genotype-by-treatment interaction for EOT abstinence (χ2 = 10.7, degrees of freedom = 2. P = 0.0049): specifically, cNRT was more effective in smokers with rs16969968 GG genotype than was placebo, while varenicline was more effective in smokers of GA/AA genotypes. In EA ancestry smokers, there was no significant genotype-by-treatment interaction. In the whole sample, although both were effective at EOT, only varenicline, and not cNRT, was significantly effective relative to placebo at 6-month follow-up. Importantly, this study suggests that genetic information can further enhance smoking cessation treatment effectiveness.
AB - It is unclear if genetic variants affect smoking cessation treatment response. This study tested whether variants in the cholinergic receptor nicotinic alpha 5 subunit (CHRNA5) predict response to smoking cessation medication by directly comparing the two most effective smoking cessation pharmacotherapies. In this genotype-stratified randomized, double-blind, placebo-controlled clinical trial (May 2015–August 2019 in St Louis, Missouri), smokers were randomized by genotype in blocks of six (1:1:1 ratio) to three conditions: 12 weeks of placebo (n = 273), combination nicotine patch and lozenge (combination nicotine replacement therapy, cNRT, n = 275), or varenicline (n = 274). All participants received counseling and were followed for 12 months. The primary end point was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT, week 12). Trial registration and eligibility criteria are on clinicaltrials.gov (https://clinicaltrials.gov/) (NCT02351167). We conducted the genetic analyses separately for 516 European ancestry (EA) smokers and 306 non-EA smokers (including 270 African American smokers). In African American smokers, there was a genotype-by-treatment interaction for EOT abstinence (χ2 = 10.7, degrees of freedom = 2. P = 0.0049): specifically, cNRT was more effective in smokers with rs16969968 GG genotype than was placebo, while varenicline was more effective in smokers of GA/AA genotypes. In EA ancestry smokers, there was no significant genotype-by-treatment interaction. In the whole sample, although both were effective at EOT, only varenicline, and not cNRT, was significantly effective relative to placebo at 6-month follow-up. Importantly, this study suggests that genetic information can further enhance smoking cessation treatment effectiveness.
UR - http://www.scopus.com/inward/record.url?scp=85088993442&partnerID=8YFLogxK
U2 - 10.1002/cpt.1971
DO - 10.1002/cpt.1971
M3 - Article
C2 - 32602170
AN - SCOPUS:85088993442
SN - 0009-9236
VL - 108
SP - 1315
EP - 1325
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 6
ER -