Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data.

Geik Yong Ang,Choo Yee Yu,Mohd Ikhmal Hanif Abdul Khalid,Tuan Azlin Tuan Abdu Aziz,Aminuddin Ahmad,Richard Johari James,Fadzilah Mohd Nor,Mohd Zaki Salleh,Thuhairah Abdul Rahman,Kamarudzaman Md Isa,Adzrool Idzwan Ismail,Hood Salleh,Vinothini Subramaniam,Lay Kek Teh,Kent E Vrana

doi:10.1371/journal.pone.0164169

Abstract

The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme’s activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.

Highlights

Genetic factors are known to contribute towards interindividual variation in drug disposition mutations that occur in genes that encode for drug-metabolizing cytochrome P450 (CYP) enzymes [1]
A total of 115 CYP genes comprising of active and pseudogenes were discovered following the release of the complete human genome sequence but 90% of drug metabolism activities are attributed to a small number of core enzymes including CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 [4, 5]
We found 449 CYP2C19 genetic variants in the Orang Asli genomes and 70 of these polymorphisms have not been reported in Database of Single Nucleotide Polymorphisms (dbSNP) build 146

Summary

Introduction

Genetic factors are known to contribute towards interindividual variation in drug disposition mutations that occur in genes that encode for drug-metabolizing cytochrome P450 (CYP) enzymes [1]. A total of 115 CYP genes comprising of active and pseudogenes were discovered following the release of the complete human genome sequence but 90% of drug metabolism activities are attributed to a small number of core enzymes including CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 [4, 5]. Preemptive genotyping of genes that are known to be involved in the metabolism of a particular drug may minimize the risk of adverse drug reaction by allowing drug selection and dosage adjustment to be carried out based on the patient’s inferred phenotype before the initiation of treatment [7]

Methods

Results

Conclusion