Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) in the prediction of smoking quantity, smoking cessation, and response to cessation medication in multiple studies of smoking cessation. Three common haplotypes (low-risk, intermediate-risk, and high-risk) in the CHRNA5-CHRNA3-CHRNB4 region are defined by rs16969968 and rs680244. The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predict a later age of smoking cessation in a community-based sample. In a smoking cessation trial, these variants predict abstinence at end of treatment in individuals receiving placebo medication, but not amongst individuals receiving active medication. Pharmacological treatments moderate the genetic risk in affecting cessation success. These pharmacogenetic interactions have been reproduced by a recent meta-analysis of smoking cessation trials. The number needed to treat (NNT) is 4 for smokers with the high-risk haplotype, 7 for smokers with the intermediate-risk haplotype, and >1000 for smokers with the low-risk haplotype. The wide variation in NNT between smokers with different haplotypes supports the notion that personalized smoking cessation intervention based upon genotype could meaningfully increase the efficiency of such treatment. In summary, variants in the CHRNA5-CHRNA3-CHRNB4 region identify individuals at increased risk of cessation failure, and this increased risk can be ameliorated by cessation pharmacotherapy.

中文翻译：

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基因组学和个性化医疗：CHRNA5-CHRNA3-CHRNB4 和戒烟治疗

吸烟非常容易上瘾，现代基因研究已经确定了对尼古丁依赖的强大遗传影响。转化这些遗传发现的一个重要步骤是确定影响戒烟的遗传因素，以加强当前的戒烟治疗。我们回顾了烟碱受体基因簇 (CHRNA5-CHRNA3-CHRNB4) 中的变异在多项戒烟研究中预测吸烟量、戒烟和戒烟药物反应的重要性。CHRNA5-CHRNA3-CHRNB4 区域中的三种常见单倍型（低风险、中风险和高风险）由 rs16969968 和 rs680244 定义。CHRNA5-CHRNA3-CHRNB4 区域中预测尼古丁依赖的遗传变异也预测了社区样本中较晚的戒烟年龄。在戒烟试验中，这些变体预测接受安慰剂药物治疗的个体在治疗结束时戒烟，但不能预测接受活性药物治疗的个体。药物治疗可减轻影响戒烟成功的遗传风险。最近对戒烟试验的荟萃分析再现了这些药物遗传学相互作用。高危单倍型吸烟者需要治疗的数量 (NNT) 为 4，中危单倍型吸烟者为 7，低危单倍型吸烟者为 >1000。具有不同单倍型的吸烟者之间 NNT 的广泛差异支持这样一种观点，即基于基因型的个性化戒烟干预可以有意义地提高这种治疗的效率。总之，