Genetic Polymorphisms and In Silico Mutagenesis Analyses of CYP2C9, CYP2D6, and CYPOR Genes in the Pakistani Population.

Shabbir Ahmed,Jie Zhou,Zhan Zhou,Shu-Qing Chen

doi:10.3390/genes9100514

Abstract

Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals’ venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.

Highlights

Genetic constitution determines the varied interethnic metabolizing capacities of various drug metabolizing enzymes [1]
We investigated the genotype and allele frequencies in CYP2C9, CYP2D6 and Cytochrome P450 oxidoreductase (CYPOR) genes, and compared our findings with 11 corresponding world populations reported in the 1000 Genomes
This approach has already been practiced in various human genes to determine numerous polymorphisms and to identify individual’s single nucleotide polymorphisms (SNPs) associations to disease phenotypes [40,41]

Summary

Introduction

Genetic constitution determines the varied interethnic metabolizing capacities of various drug metabolizing enzymes [1]. The recent developments in the pharmacogenomics field revealed that polymorphisms in DNA sequences identified as single nucleotide polymorphisms (SNPs) may elucidate some of the variability in drug metabolizing enzyme activities These variations in DNA sequences contribute to inappropriate therapeutic responses in different ethnic groups. The metabolic capabilities of these enzymes can range from completely lacking to ultrahigh activity, depending on its variation type Examples of these types include copy number variations (CNVs), insertions and/or deletions (INDELs), and single nucleotide substitutions (SNSs) in protein-encoding genes. The basic phenotype or genotype findings have greatly contributed to the determination of an individual’s metabolic capacity that acts as an important tool for safe and rational drug administration In the future, this practice will be beneficial to decrease the prevalence of adverse drug reactions and treatment failures for narrow therapeutic index drugs (NTI-drugs) [2]

Methods

Results

Conclusion