Dataset Information

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

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.

SUBMITTER: Claudio-Campos K

PROVIDER: S-EPMC6739902 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Claudio-Campos Karla K Moneró-Paredes Mariangeli M Hernández Eliud E Renta Jessicca J Duconge Jorge J

Pharmacogenomics 20190801 12

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 ...[more]

PMID: 31453773

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Project description:Since the first Spanish settlers brought horses to America centuries ago, several local varieties and breeds have been established in the New World. These were generally a consequence of the admixture of the different breeds arriving from Europe. In some instances, local horses have been selectively bred for specific traits, such as appearance, endurance, strength, and gait. We looked at the genetics of two breeds, the Puerto Rican Non-Purebred (PRNPB) (also known as the "Criollo") horses and the Puerto Rican Paso Fino (PRPF), from the Caribbean Island of Puerto Rico. While it is reasonable to assume that there was a historic connection between the two, the genetic link between them has never been established. In our study, we started by looking at the genetic ancestry and diversity of current Puerto Rican horse populations using a 668 bp fragment of the mitochondrial DNA D-loop (HVR1) in 200 horses from 27 locations on the island. We then genotyped all 200 horses in our sample for the "gait-keeper" DMRT3 mutant allele previously associated with the paso gait especially cherished in this island breed. We also genotyped a subset of 24 samples with the Illumina Neogen Equine Community genome-wide array (65,000 SNPs). This data was further combined with the publicly available PRPF genomes from other studies. Our analysis show an undeniable genetic connection between the two varieties in Puerto Rico, consistent with the hypothesis that PRNPB horses represent the descendants of the original genetic pool, a mix of horses imported from the Iberian Peninsula and elsewhere in Europe. Some of the original founders of PRNRB population must have carried the "gait-keeper" DMRT3 allele upon arrival to the island. From this admixture, the desired traits were selected by the local people over the span of centuries. We propose that the frequency of the mutant "gait-keeper" allele originally increased in the local horses due to the selection for the smooth ride and other characters, long before the PRPF breed was established. To support this hypothesis, we demonstrate that PRNPB horses, and not the purebred PRPF, carry a signature of selection in the genomic region containing the DMRT3 locus to this day. The lack of the detectable signature of selection associated with the DMRT3 in the PRPF would be expected if this native breed was originally derived from the genetic pool of PRNPB horses established earlier and most of the founders already had the mutant allele. Consequently, selection specific to PRPF later focused on allels in other genes (including CHRM5, CYP2E1, MYH7, SRSF1, PAM, PRN and others) that have not been previously associated with the prized paso gait phenotype in Puerto Rico or anywhere else.

Dataset Information

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

Publications

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

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