Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, RI.
Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI.
Nicotine Tob Res. 2019 Aug 19;21(9):1289-1293. doi: 10.1093/ntr/ntz009.
Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation.
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, replicated non-single nucleotide polymorphisms, and/or the nicotine metabolite ratio. We estimated the genotype × treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups.
We identified 18 trials (N = 9017 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 6-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 with placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both 6-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% confidence interval [CI] = 1.19 to 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.
We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate.
Although we identified some evidence of genotype × 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.
药物基因组学研究利用遗传变异来识别可能对戒烟药物治疗有反应的吸烟者。
我们对戒烟药物治疗试验的主要和次要分析进行了系统评价和荟萃分析。符合条件的试验需有关于预先选择的单核苷酸多态性、复制的非单核苷酸多态性和/或尼古丁代谢物比的数据。我们估计基因型-治疗相互作用为基因型组之间治疗效果的风险比（RRR）比值。
我们确定了 18 项试验（N=9017 名参与者），包括 40 项活性（安非他酮、尼古丁替代疗法[NRT]、伐伦克林或联合疗法）与安慰剂的比较和 16 项活性与活性的比较。在非西班牙裔黑人和非西班牙裔白种人吸烟者的 6 个月戒烟和治疗结束时戒烟以及非西班牙裔白种人吸烟者的治疗结束时戒烟方面，CHRNA5 中的 rs16969968 基因型存在统计学上的异质性。在 CHRNA3 中的 rs1051730 基因型方面，非西班牙裔白种人吸烟者的治疗结束时也存在异质性。其他基因型-治疗组合则没有明显的统计学证据。与安慰剂相比，NRT 在非西班牙裔黑种人吸烟者中 rs16969968-GG 基因型下，6 个月戒烟（GG 与 GA 或 AA 的 RRR，3.51；95%置信区间[CI] = 1.19 至 10.30）和治疗结束时戒烟（GG 与 GA 或 AA 的 RRR，5.84；95%CI = 1.89 至 18.10）更有效。在非西班牙裔白种吸烟者中，NRT 相对于安慰剂的有效性在 rs1051730 和 rs16969960 基因型方面相似。
我们没有发现基于基因型的戒烟药物治疗效果的广泛差异。证据质量普遍为中等。
尽管我们发现了一些基因型-治疗相互作用的证据，但绝大多数分析并没有提供基因型差异治疗反应的证据。在我们发现一些证据的地方，由于每个基因型比较的试验数量少、置信区间宽以及证据质量中等，这些结果应被视为初步结果，并谨慎解释。需要通过建模来评估治疗效果的异质性的前瞻性试验和个体化患者数据荟萃分析，以评估遗传信息生物标志物对戒烟药物治疗选择的临床应用价值。
