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

• Published in: PloS one 2016-10, Vol.11 (10), p.e0164169-e0164169
• Main Authors: Ang, Geik Yong, Yu, Choo Yee, Subramaniam, Vinothini, Abdul Khalid, Mohd Ikhmal Hanif, Tuan Abdu Aziz, Tuan Azlin, Johari James, Richard, Ahmad, Aminuddin, Abdul Rahman, Thuhairah, Mohd Nor, Fadzilah, Ismail, Adzrool Idzwan, Md Isa, Kamarudzaman, Salleh, Hood, Teh, Lay Kek, Salleh, Mohd Zaki
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Alleles; Analysis; Antidepressants; Asian Continental Ancestry Group - genetics; Binding sites; Biology and Life Sciences; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P450; Drug metabolism; Enzymes; Exons; Female; Gene sequencing; Genes; Genetic aspects; Genetic diversity; Genetic variance; Genetic Variation; Genotype; Genotype & phenotype; Genotypes; Genotyping; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Introns; Linkage Disequilibrium; Malaysia; Male; Medicine and Health Sciences; Metabolism; Middle Aged; Multiprocessing; Mutation; Nomenclature; Pain; People and Places; Pharmacy; Polymorphism, Single Nucleotide; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164169

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.