Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, USA.
Department of Pharmacology & Toxicology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936-5067, USA.
Pharmacogenomics. 2019 Aug;20(12):891-902. doi: 10.2217/pgs-2019-0051.
Perform predictions of functional consequences of variants identified by next-generation sequencing in Puerto Ricans. Identified low-frequency variants (minor allele frequencies <2%) were evaluated using the Combined Annotation-Dependent Depletion (CADD v1.3) tools and molecular modeling/docking analysis to predict impact on CYP2C9 activity. ,,,, and a novel induce conformational changes that affect the binding site of -warfarin. Most of these deleterious variants occur at higher frequency among individuals with large African ancestry. The unfavorable distance of -warfarin from heme group, and low-binding interactions due to these variants, suggest major complications during warfarin therapy. This study contributes to the field by predicting functional alterations of rare variants for the first time in Hispanics.
对波多黎各人进行下一代测序鉴定的功能后果进行预测。使用联合注释依赖性耗竭 (CADD v1.3) 工具和分子建模/对接分析评估鉴定的低频变异体（次要等位基因频率 <2%），以预测对 CYP2C9 活性的影响。、、和一个新的变体导致构象变化，影响-warfarin 的结合位点。这些有害变体中的大多数在具有大量非洲血统的个体中发生频率更高。-warfarin 与血红素基团的不利距离，以及由于这些变体导致的低结合相互作用，表明华法林治疗期间存在严重并发症。这项研究通过首次在西班牙裔人群中预测罕见变体的功能改变，为该领域做出了贡献。
