Genetic Variant in CHRNA5 and Response to Varenicline and Combination Nicotine Replacement in a Randomized Placebo-Controlled Trial

Abstract

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.

Figure 1 –

Consort Diagram. *full exclusion criteria are available at clinicaltrials.gov, identifier NCT02351167

Figure 2 –

Abstinence by treatment group at 12 weeks (end of treatment) and 6 months for the entire sample, and stratified by race N=822, 516 smokers of European Ancestry, 306 smokers of non-European Ancestry. (A) Abstinence at end of treatment. (A1) Abstinence at end of treatment stratified by race. (B) Abstinence at 6 months. (B1) Abstinence at 6 month stratified by race.

Figure 3 –

Quit rate at 12 weeks (end of treatment) in each genotype group (CHRNA5 rsl6969968) in European and African American Ancestry smokers (A) All smokers stratified by race. (B) EA: N=516. Gene by Treatment Interaction Wald X²=0.20, df=2, p=0.91. (C) AA: N=270. Gene by Treatment Interaction X²=10.7, df=2, p=0.0049

Figure 4 –

Abstinence at 6 months in each genotype group (CHRNA5 rsl6969968) in European and African American Ancestry smokers (A) All smokers stratified by race. (B) All smokers of European Ancestry N-516. No gene-by-treatment interaction X²=0.93, df=2, p=0.63. (C) All smokers of African American Ancestry, N=270. Gene by treatment interaction X²=4.96, df=2, p=0.084

Figure 5 –

Quit rate at 12 weeks (end of treatment) in each genotype group (CHRNA5 rsl6969968) in European and non-European Ancestry smokers (A) All smokers stratified by race. (B) EA: N=516. Gene by Treatment Interaction Wald X²=0.20, df=2, p=0.91. (C) Non-EA: N=306 Gene by Treatment Interaction X²=11.4, df=2, p=0.0033