Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent
Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent
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DOI：
10.1038/s41380-020-0702-z
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发表时间：
2020-03-10
影响因子：
11
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
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作者：
Buchwald, Jadwiga;Chenoweth, Meghan J.;Tyndale, Rachel F.
吸烟行为，包括吸烟量、戒烟和烟草相关疾病，都受到尼古丁清除率的影响。尼古丁清除率可以通过尼古丁代谢物比率（NMR）（3′羟基可替宁/可替宁的比率）来估计，但仅适用于当前吸烟者。推进这种高度遗传的CYP2A6生物标志物（尼古丁的主要代谢酶）的基因组学研究，也将使从不吸烟者和曾经吸烟者的研究成为可能。我们进行了迄今为止最大的全基因组关联研究（GWAS），在欧洲血统的当前吸烟者（n = 5185）中发现了1255个全基因组显著变异，并复制了19号染色体位点。19号染色体的精细定位揭示了13个推定的因果变异，其中9个是高度推定的因果变异，与CYP2A6、MAP3K10、ADCK4和CYP2B6有关。我们还在4号染色体上发现了一个推测的与TMPRSS11E相关的变异，并证明TMPRSS11E变异与UGT2B17活性表型之间存在关联。这14个假定的因果snp加在一起，解释了38%的核磁共振变异，从之前解释的20%到30%的相似性显著增加。我们对尼古丁摄入生物标志物的额外GWASs表明，可替宁和吸烟强度（可替宁/香烟/天（CPD））与NMR共享19号染色体和4号染色体位点，可替宁和更准确的生物标志物，可替宁+ 3′羟基可替宁，与CPD和包年（即累积暴露）共享CHRNA5附近的第15号染色体位点。了解影响吸烟相关特征的遗传因素有助于对吸烟和疾病进行流行病学研究，并有助于优化戒烟支持，从而减少与吸烟相关的巨大个人和社会成本。
Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3 ' hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained similar to 38% of NMR variation, a substantial increase from the similar to 20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3 ' hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.