Low-frequency variants at the CYP2C9 locus among Puerto Rican patients on warfarin: in silico predictions of functionality and conservation

: 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.