Phenotype prediction and characterization of 25 pharmacogenes in Thais from whole genome sequencing for clinical implementation

Abstract

Publicly available pharmacogenomics (PGx) databases enable translation of genotype data into clinically actionable information. As variation within pharmacogenes is population-specific, this study investigated the spectrum of 25 clinically relevant pharmacogenes in the Thai population (n = 291) from whole genome sequencing. The bioinformatics tool Stargazer was used for phenotype prediction, through assignment of alleles and detection of structural variation. Known and unreported potentially deleterious PGx variants were identified. Over 25% of Thais carried a high-risk diplotype in CYP3A5, CYP2C19, CYP2D6, NAT2, SLCO1B1, and UGT1A1. CYP2D6 structural variants accounted for 83.8% of all high-risk diplotypes. Of 39 known PGx variants identified, six variants associated with adverse drug reactions were common. Allele frequencies of CYP3A5*3 (rs776746), CYP2B6*6 (rs2279343), and NAT2 (rs1041983) were significantly higher in Thais than East-Asian and global populations. 121 unreported variants had potential to exert clinical impact, majority were rare and population-specific, with 60.3% of variants absent from gnomAD database. This study demonstrates the population-specific variation in clinically relevant pharmacogenes, the importance of CYP2D6 structural variation detection in the Thai population, and potential of unreported variants in explaining drug response. These findings are essential in development of dosing guidelines, PGx testing, clinical trials, and drugs.

Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach

“…Genetic polymorphisms of the CYP3A gene were reported in the Thai population (Mauleekoonphairoj et al, 2020). CYP3A4 polymorphisms are rarely found in Asians, whereas 65-85% of Asians have CYP3A5*3 (Lamba et al, 2002;Hutchison and O'Brien, 2007;Zhou et al, 2017;Mauleekoonphairoj et al, 2020).…”

“…Genetic polymorphisms of the CYP3A gene were reported in the Thai population (Mauleekoonphairoj et al, 2020). CYP3A4 polymorphisms are rarely found in Asians, whereas 65-85% of Asians have CYP3A5*3 (Lamba et al, 2002;Hutchison and O'Brien, 2007;Zhou et al, 2017;Mauleekoonphairoj et al, 2020). Although some studies indicated that polymorphisms of CYP3A4/5 might affect the clearance of their substrate such as tacrolimus, the genetic variation in CYP3A enzymes has no significant correlation with in vivo MDZ metabolism and disposition (He et al, 2005;Miao et al, 2009;Singh et al, 2009).…”

“…The genotyping methods together with the genetic variation in SLCO1B1 c.521T > C (rs4149056), c.388A > G (rs2306283), g.-11187G > A (rs4149015), and ABCG2 c.421C > A (rs2231142) of all study participants have previously been reported (Rattanacheeworn et al, 2020). In addition, as genetic variation in CYP3A was reported in the Thai population (Mauleekoonphairoj et al, 2020), genotyping for CYP3A5*3 c.6986A > G (rs776746) was also carried out in all participants. Supplementary Table S3 summarized the distribution and the genotyping method of CYP3A5*3 in this study.…”

Genetic landscape of 125 pharmacogenes in Chinese from the Chinese Millionome Database

“…3 b), which suggested the necessity to focus on the rare pharmacogenes variants in studying inter-individual variability in drug response. Analysis of 25 clinically relevant pharmacogenes in 291 genomes of the Thai population identified 121 putatively functional variants, majority of which were rare and specific to the Thais but absent from gnomAD database 20 . As more and more rare pharmacogene variants were found, the method to interpret their clinical implication were needed to be developed urgently 21 , 22 .…”

Genetic risks and association with severe COVID-19 among global populations

“…These studies examined mostly European populations, which prompted us to examine these disease-modifying loci in the Asian population. We examined variabilities in the frequencies of risk alleles among the global population from the gnomAD, GenomeAsia 100k, and Southeast Asia database [5].…”