Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes.
Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes.
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DOI：
10.1111/cts.13135
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
El-Boraie A;Tanner JA;Zhu AZX;Claw KG;Prasad B;Schuetz EG;Thummel KE;Fukunaga K;Mushiroda T;Kubo M;Benowitz NL;Lerman C;Tyndale RF
CYP 2A 6活性（通过尼古丁代谢物比率（NMR）进行表型分析）是几种吸烟行为的预测因子，包括戒烟和吸烟相关疾病风险。NMR的遗传率为60- 80%，但基于常见变异的加权遗传风险评分（wGRS）仅解释了30- 35%。假设罕见的变异（次要等位基因频率<1%）可以解释这种缺失的遗传力。我们提出了两项靶向测序研究，其中罕见的蛋白质编码变体在体内、计算机模拟和体外进行了功能表征，以检验这一假设。在一项戒烟试验中，对1687名个体进行了测序;表征措施包括体内核磁共振、体外蛋白质表达和从重组蛋白测量的代谢活性。在人类肝脏库中，对312个人类肝脏样本进行测序;测量包括提取的肝脏组织的RNA表达、蛋白质表达和代谢活性。总共发现了47种罕见编码变体中的38种是新的;特征范围从功能获得到功能丧失。在群体水平上，由罕见编码变体解释的NMR变异部分很小（~1%）。然而，掺入后，对于具有罕见蛋白质编码变体的个体（即，残差减少），大约三分之一的个体（12/39）从正常状态重新分配为慢代谢状态。罕见的编码变体可以改变个体的CYP 2A 6活性;通过精确的功能表征将其整合到wGRS中对于准确评估临床结果和实现所有人的精准医学是必要的。对非编码变异的调查是必要的，以进一步解释NMR中缺失的遗传性。
CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein‐coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain‐of‐function to loss‐of‐function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein‐coding variants (i.e., the residuals were reduced), and approximately one‐third of these individuals (12/39) were re‐assigned from normal to slow metabolizer status. Rare coding variants can alter an individual’s CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.
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影响因子：
6.7
作者：
El-Boraie A;Chenoweth MJ;Pouget JG;Benowitz NL;Fukunaga K;Mushiroda T;Kubo M;Nollen NL;Sanderson Cox L;Lerman C;Knight J;Tyndale RF
通讯作者：
Tyndale RF
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通讯作者：
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影响因子：
6.7
作者：
Dempsey, D;Tutka, P;Benowitz, NL
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Benowitz, NL