Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.

中文翻译：

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来自死后样本的曲马多代谢的全基因组关联研究。

I 期曲马多代谢需要细胞色素 p450 家族 2、亚家族 D、多肽 6 (CYP2D6) 才能形成 O-去甲基曲马多 (M1)。CYP2D6 基因变异可能推断代谢者表型；然而，药物 ADME（吸收、分布、代谢和排泄）和反应取决于蛋白质途径，而不是单独的 CYP2D6。关于药物暴露后反式作用蛋白对异质表型的贡献的数据很少。一项全基因组关联研究确定了与曲马多转化为 M1 (M1:T) 相关的五个标记（rs79983226/kgp11274252、rs9384825、rs62435418/kgp10370907、rs72732317/kgp3743668 和 rs184199168/exm1592932）。这些 SNP 存在于先前与不良反应有关的五个基因中。对随附毒理学元数据的分析显示，M1:T 与样品多药性程度之间存在显着的正线性关系。总之，这些数据确定了暴露于曲马多后潜在临床表型推断的候选基因座，并强调了样本多药治疗作为死后遗传学研究中可能的诊断协变量。