PDF(Pubmed)
Abstract：
CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3\'-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10-6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10-5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10-4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource.
摘要：
CYP2A6，一种遗传可变酶，尼古丁失活,激活致癌物,代谢许多药物。CYP2A6的变化影响吸烟行为和烟草相关疾病风险。这项全表型关联研究检查了我们的CYP2A6活性的加权遗传风险评分（wGRS）的重建版本与英国生物库（N=395887）中的疾病之间的关联。然后使用wGRS作为仪器，在两个样本孟德尔随机化中估计了表型CYP2A6活性（以尼古丁代谢物比例：3'-羟基可替宁/可替宁测量）对表型全显著（PWS）信号的因果关系。在生存分析中，比较了PWS信号的较快CYP2A6代谢者与较慢CYP2A6代谢者之间的诊断时间年龄。在总样本中，确定了六个PWS信号：两个肺癌和四个阻塞性呼吸系统疾病PheCodes，其中较快的CYP2A6活性与较高的疾病风险相关（Ps<1×10-6）。发现CYP2A6与吸烟状态的显着交互作用（Ps交互作用<0.05）；在当前吸烟者中，在整个组中发现了相同的六个PWS信号，而在以前或从未吸烟者中未发现PWS信号。在总样本和当前吸烟者中，在孟德尔随机化中，对六个PWS信号的CYP2A6活性因果估计是显着的（Ps<5×10-5）。此外,对于6个PWS信号,较快的CYP2A6代谢状态与较年轻的疾病诊断年龄相关(在当前吸烟者中,Ps<5×10-4).这些发现支持CYP2A6活性加快作为当前吸烟者肺癌和阻塞性呼吸系统疾病的因果危险因素的作用。这些疾病的发病更年轻。这项研究利用了英国生物库资源。
