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

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

<i>CYP2C19</i> genotype frequencies in the Orang Asli.

<p><i>CYP2C19</i> genotype frequencies in the Orang Asli.</p

Comparison of <i>CYP2C19</i> allele frequencies between the Orang Asli and various populations.

<p>Comparison of <i>CYP2C19</i> allele frequencies between the Orang Asli and various populations.</p

Detection of <i>CYP2C19</i> Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data

<div><p>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 <i>CYP2C19</i> 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 <i>CYP2C19*3</i> (6.5%), <i>*2</i> (5.7%) and <i>*35</i> (2.4%) whereas allele with increased function <i>*17</i> 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 <i>CYP2C19</i> 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 <i>CYP2C19</i> will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.</p></div

Analysis of haplotype structures at CYP2C19 locus in the Orang Asli.

<p>(a) Linkage disequilibrium map showing 19 haplotype blocks along with the reference SNP cluster ID (rs). Bright red depicts very strong LD (LOD ≥2; D’ = 1), pink red (LOD ≥2; D’ < 1) and blue (LOD < 2; D’ = 1) for intermediate LD and white for no LD (LOD < 2, D’ < 1) between the pair of SNPs. Numbers in the square were the D’ value multiplied by 100. (b) Haplotype structures of CYP2C19 with tagged SNP indicated by an inverted triangle. Frequency of each haplotype is shown at the edge and the multi-allelic D’ value between each block is shown beneath. The most common crossings between haplotypes are indicated by thick lines whereas less common crossings are indicated by thinner lines.</p

Allele frequencies of <i>CYP2C19</i> in the Orang Asli.

<p>Allele frequencies of <i>CYP2C19</i> in the Orang Asli.</p