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, andRYR1, 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 includingSLCO1B3(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%), andSLCO1B1(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.

Purpose: Pharmacogenes have an influence on biotransformation pathway and clinical outcome of primaquine and chloroquine which are often prescribed to treat Plasmodium vivax infection. Genetic variation may impact enzyme activity and/or transporter function and thereby contribute to relapse. The aim of the study was to assess allele, genotype frequencies and the association between pharmacogenes variation and primaquine response in Thai patients infected with Plasmodium vivax. Patients and Methods: Fifty-one patients were genotyped for 74 variants in 18 genes by Sequenom MassARRAY^® and Taqman^® SNP Real-Time PCR. Results: SNP frequencies were not significantly different between relapse (n=4) and non-relapse (n=47) patients. However, the CYP2C19 c.681G>A, the frequency of the A-allele that defines the non-functional CYP2C19*2 haplotype was significantly higher compared to the G-allele (OR=5.14, p=0.021). Patients heterozygous for ABCG2 c.421C>A had a higher odds ratio (OR=8.75, p=0.071) and the frequency of the G-allele of UGT2B7 c.372G>A was higher compared to the A-allele (OR=3.75, p=0.081). CYP2C19, ABCG2 and UGT2B7 emerged as potential high priority genes. Conclusion: Decreased activity of CYP2C19, ABCG2 and UGT2B7 in combination with CYP2D6 intermediate or poor metabolizer status may expose patients to a higher risk of Plasmodium vivax relapse. Further investigations are warranted to substantiate these findings.

Purpose: Plasma efavirenz (EFV) concentrations within therapeutic levels are essential to successfully treat patients suffering from human immunodeficiency virus (HIV) type 1. In addition to the drug-metabolizing enzyme CYP2B6, other phase II drug-metabolizing enzymes and transporters may have an important role in the pharmacokinetics of EFV. Thus, the influence of phase II drug-metabolizing enzymes and drug transporters on plasma EFV levels was investigated in Thai HIV patients receiving EFV. Patients and Methods: Genotyping was performed by TaqMan^® real-time PCR in 149 HIV-infected Thai adults, and plasma efavirenz concentration was measured by a validated high-performance liquid chromatography in 12 hours after dosing steady-state plasma samples at week 12 and 24. Results: Patients with three or more copies of SULT1A1 had significantly lower median plasma EFV concentrations than those carrying two copies at week 12 (p=0.046) and SULT1A1*2 (c.638G>A) carriers had significantly lower median plasma EFV concentrations compared to those not carrying the variant at week 24 (p=0.048). However, no significant association was found after adjusting for CYP2B6 genotype. Conclusion: Genetic variation in a combination of SULT1A1*2 and SULT1A1 copy number may contribute to variability in EFV metabolism and thereby may impact drug response. The influence of a combination between the SULT1A1 and CYP2B6 genotype on EFV pharmacokinetics should be further investigated in a larger study population.

Purpose: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants. Materials and Methods: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG^® v.3). Steady-state trough plasma donepezil concentrations were measured using high-performance liquid chromatography. Results: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59– 87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44– 67.65) ng/mL vs 61.95 (35.25– 97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r² = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r² = 0.49). Conclusion: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.

Introduction: Genetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene and ATP-binding cassette subfamily G member 2 (ABCG2) gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment. Purpose: We explored allele and genotype frequencies of SLCO1B1 and ABCG2 genes including their predicted phenotypes in 53 Thai participants. Of these, 17 had chronic kidney disease and were on statins. Materials and Methods: Genotyping analysis for SLCO1B1 c.521T>C (rs4149056), c.388A>G (rs2306283), g.-11187G>A (rs4149015), and ABCG2 c.421C>A (rs2231142) was done by using TaqMan^® Real time PCR. All were tested for Hardy–Weinberg Equilibrium. Results: Most of the participants (80%) had normal function haplotypes SLCO1B1 (*1A and *1B) while decreased (*5, *15, and *17) and unknown (*21) function haplotypes were less observed. Four phenotypes of SLCO1B1 were observed: 69.81% had normal function (*1A/*1A,*1A/*1B, and *1B/*1B), 13.21% had intermediate function (*1A/*17, *1B/*15 and *1B/*17), 9.43% had indeterminate function (*1A/*21 and *1B/*21) and 7.55% had low function (*5/*15, *15/*15, and *15/*17). ABCG2 c.421A allele frequency was 25%. The frequency of ABCG2 c.421CA and AA phenotypes were 37.7% and 5.7%, respectively. The allele and genotype frequencies observed are consistent with reports in Asians. However, there were differences in major allele distributions between Asians and Caucasians for SLCO1B1 c.388A>G; SLCO1B1 c.388G were highly found in Asians, but c.388A were more observed in Caucasians. Conclusion: This study showed that in the Thai population, there were 4 SNPs of SLCO1B1 and ABCG2 genes. This finding may be clinically applied to minimize inter-individual variability of drugs such as statins and allopurinol. Further study with a larger sample size is needed to assess the drug profiles and responses to treatment.