Karla Claudio-Campos1, Mariangeli Moneró-Paredes2, Eliud Hernández3, Jessicca Renta4, Jorge Duconge3. 1. Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, USA. 2. Department of Pharmacology & Toxicology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936-5067, USA. 3. Department of Pharmaceutical Sciences, Medical Sciences Campus, School of Pharmacy, University of Puerto Rico, San Juan, PR 00936-5067, USA. 4. Department of Biochemistry, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936-5067, USA.
Abstract
Aim: Perform in silico predictions of functional consequences of CYP2C9 variants identified by next-generation sequencing in Puerto Ricans. Methods: Identified low-frequency CYP2C9 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. Results: CYP2C9*5,*8,*9,*11,*12,*21 and a novel *61 induce conformational changes that affect the binding site of S-warfarin. Most of these deleterious variants occur at higher frequency among individuals with large African ancestry. Conclusion: The unfavorable distance of S-warfarin from heme group, and low-binding interactions due to these CYP2C9 variants, suggest major complications during warfarin therapy. This study contributes to the field by predicting functional alterations of rare CYP2C9 variants for the first time in Hispanics.
Aim: Perform in silico predictions of functional consequences of CYP2C9 variants identified by next-generation sequencing in Puerto Ricans. Methods: Identified low-frequency CYP2C9 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. Results:CYP2C9*5,*8,*9,*11,*12,*21 and a novel *61 induce conformational changes that affect the binding site of S-warfarin. Most of these deleterious variants occur at higher frequency among individuals with large African ancestry. Conclusion: The unfavorable distance of S-warfarin from heme group, and low-binding interactions due to these CYP2C9 variants, suggest major complications during warfarin therapy. This study contributes to the field by predicting functional alterations of rare CYP2C9 variants for the first time in Hispanics.
Entities:
Keywords:
-warfarin ; CYP2C9; Caribbean Hispanics; DNA sequencing; docking; pharmacogenetics; single nucleotide variations
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