Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population

Abstract

Differences in drug responses in individuals are partly due to genetic variations in pharmacogenes, which differ among populations. Here, genome sequencing of 171 unrelated Thai individuals from all regions of Thailand was used to call star alleles of 51 pharmacogenes by Stargazer, determine allele and genotype frequencies, predict phenotype and compare high-impact variant frequencies between Thai and other populations. Three control genes, EGFR, VDR, and RYR1, were used, giving consistent results. Every individual had at least three genes with variant or altered phenotype. Forty of the 51 pharmacogenes had at least one individual with variant or altered phenotype. Moreover, thirteen genes had at least 25% of individuals with variant or altered phenotype including SLCO1B3 (97.08%), CYP3A5 (88.3%), CYP2C19 (60.82%), CYP2A6 (60.2%), SULT1A1 (56.14%), G6PD (54.39%), CYP4B1 (50.00%), CYP2D6 (48.65%), CYP2F1 (46.41%), NAT2 (40.35%), SLCO2B1 (28.95%), UGT1A1 (28.07%), and SLCO1B1 (26.79%). Allele frequencies of high impact variants from our samples were most similar to East Asian. Remarkably, we identified twenty predicted high impact variants which have not previously been reported. Our results provide information that contributes to the implementation of pharmacogenetic testing in Thailand and other Southeast Asian countries, bringing a step closer to personalized medicine.

An increase in urinary primaquine and a reduction in urinary primaquine-5,6-orthoquinone in the Thai population with CYP2D6 reduced enzyme function

“…The frequency of CYP2D6 alleles in our study was similar to previous reports in the Thai population [ [13] , [14] , [15] , [16] , [17] , [18] , [19] ]. Furthermore, the proportions of CYP2D6 IM and CYP2D6 NM were consistent with those reported in Asians [ 21 ].…”

“…CYP2D6*2, CYP2D6*4, CYP2D6*5, and CYP2D6*10 were genotyped according to previous reports in Thai populations [ [13] , [14] , [15] , [16] , [17] , [18] , [19] ]. The SNPs included 2850C > T (rs16947), 4180G > C (rs1135840), 100C > T (rs1065852), and 1846G > A (rs3892097).…”

“…CYP2D6*1 and CYP2D6*2 are considered functional alleles of CYP2D6 [ 11 , 12 ]. A previous study in Thai populations reported many genetic variations of CYP2D6 , including a reduced functional allele ( CYP2D6*10 ) and nonfunctional alleles ( CYP2D6*4 and CYP2D6*5 ) [ [13] , [14] , [15] , [16] , [17] , [18] , [19] ]. In fact, CYP2D6*10 was observed in 42% and 50% of the East Asian and Thai populations, respectively [ 19 ].…”

The variation landscape ofCYP2D6in a multi-ethnic Asian population

“…*36+*10 , *10 , and *36 were more prevalent in the Chinese and Malay populations, with the Chinese and Malays exhibiting approximately six-fold higher allele frequencies of *10 compared to Indians. This trend aligns with well-documented findings, which consistently report a high prevalence of the *36+*10 tandem in East Asian populations, including Japanese, Korean, and Chinese 8,9,16 . Furthermore, it supports the common identification of the *10 allele as a reduced-function variant in Asian populations 8,9 .…”

Development of an extensive workflow for comprehensive clinical pharmacogenomic profiling: lessons from a pilot study on 100 whole exome sequencing data

“…Hence, applying multi-tools for including more genes and variants seems reasonable. So far, most studies reported the advantages of using PGx bioinformatics tools in clinical investigations but as a separate entity [ 31 , 32 ]. For those reported the multi-tool utilization, again not all of the genes in all samples were evaluated in that way [ 33 ].…”