Smoking Cessation Pharmacotherapy Based on Genetically-Informed Biomarkers: What is the Evidence?
Panagiotou OA., Schuit E., Munafò MR., Bennett DA., Bergen AW., David SP.
Introduction: Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation. Methods: We performed a systematic review and meta-analysis of primary and secondary analyses of trials of smoking cessation pharmacotherapies. Eligible were trials with data on a priori selected single nucleotide polymorphisms (SNPs), replicated nonSNP polymorphisms, and/or the nicotine metabolite ratio (NMR). We estimated the genotype-by-treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups. Results: We identified 18 trials (n=9,017 participants), including 40 active (bupropion, nicotine replacement therapy [NRT], varenicline, or combination therapies) versus placebo comparisons and 16 active versus active comparisons. There was statistical evidence of heterogeneity across rs16969968 genotypes in CHRNA5 with regard to both six-month abstinence and end-of-treatment abstinence in non-Hispanic black smokers and end-of-treatment abstinence in non-Hispanic white smokers. There was also heterogeneity across rs1051730 genotypes in CHRNA3 with regard to end-of-treatment abstinence in non-Hispanic white smokers. There was no clear statistical evidence for other genotype-by-treatment combinations. Compared to placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both six-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% CI 1.19-10.30) and end-of-treatment abstinence (RRR for GG vs. GA or AA, 5.84; 95% CI, 1.89 to 18.10). Among non-Hispanic white smokers, NRT effectiveness relative to placebo was comparable across rs1051730 and rs169969960 genotypes. Conclusions: We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate. Implications: Although we identified some evidence of genotype-by-treatment interactions, the vast majority of analyses did not provide evidence of differential treatment response by genotype. Where we find some evidence, these results should be considered preliminary and interpreted with caution because of the small number of contributing trials per genotype comparison, the wide confidence intervals, and the moderate quality of evidence. Prospective trials and individual-patient data meta-analyses accounting for heterogeneity of treatment effects through modeling are needed to assess the clinical utility of genetically-informed biomarkers to guide pharmacotherapy choice for smoking cessation.