Publications by authors named "Sukanya Wattanapokayakit"

25 Publications

  • Page 1 of 1

The Genetic Basis of Sudden Death after Covid-19 Vaccination in Thailand.

Heart Rhythm 2022 Aug 4. Epub 2022 Aug 4.

Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand. Electronic address:

Background: SAR-CoV2 vaccination reduces morbidity and mortality associated with Covid-19 disease; unfortunately, it is associated with serious adverse events, including sudden unexplained death (SUD).

Objective: We aimed to study the genetic basis of SUD after Covid-19 vaccination in Thailand.

Methods: From April to December 2021, cases with natural but unexplained death within seven days after Covid-19 vaccination were enrolled for whole exome sequencing.

Results: Thirteen were recruited, aged between 23 and 72 years, 10 (77%) were males, 12 were Thai and one was Australian. Eight (61%) died after receiving the first dose of vaccine and seven (54%) died after ChAdOx1 nCoV-19; however, there were no significant correlations between SUD and either the number or type of vaccine. Fever was self-reported in three cases. Ten (77%) and 11 (85%) died within 24 hours and 3 days after vaccination, respectively. WES analysis revealed five cases harbored SCN5A variants which had previously been identified in patients with Brugada syndrome (BrS), giving an SCN5A variant frequency of 38% (5/13). This is a significantly higher rate than observed in Thai SUD cases occurring 8 - 30 days after Covid-19 vaccination during the same period (10% (1/10)), in a Thai SUD cohort studied before the Covid-19 pandemic (12% (3/25)), and in our in-house exome database (12% (386/3231)).

Conclusions: These findings suggest that SCN5A variants may be associated with SUD within seven days after Covid-19 vaccination, regardless of vaccine type, number of vaccine dose, and presence of underlying diseases or postvaccine fever.
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http://dx.doi.org/10.1016/j.hrthm.2022.07.019DOI Listing
August 2022

Mitochondrial DNA content as a diagnostic marker for anti-tuberculosis drug-induced liver injury.

Int J Infect Dis 2022 Aug 2. Epub 2022 Aug 2.

Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.

Objectives: This study aimed to investigate whether mitochondrial DNA (mtDNA) content, an index of mitochondrial dysfunction, was associated with clinical parameters indicating ATDILI in TB patients and could emerge as an ATDILI biomarker.

Methods: Leukocyte mtDNA content in 102 TB patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 age-matched healthy controls was measured using real-time PCR.

Results: Compared to healthy controls, both TB patients with and without ATDILI had significantly decreased mtDNA content. Compared with non-ATDILI patients, mtDNA content was significantly increased in ATDILI patients. Higher mtDNA content was observed to be independently associated with increased susceptibility to ATDILI. Increased mtDNA content measured within 1-7 days of treatment was independently associated with elevated levels of serum aminotransferases assessed within 8-60 days of treatment. After initiating treatment within 1-7 days, mtDNA content was detected to be more sensitive and selective for differentiating ATDILI patients from those without ATDILI than serum aminotransferases. Kaplan-Meier analysis revealed a significant correlation between elevated mtDNA content and increased rate of ATDILI occurrence in TB patients, attested by Cox regression analysis with adjusting for confounders.

Conclusion: Changes in leukocyte mtDNA content would reflect ATDILI progression and could be used as a potential stratification tool for identifying TB patients at risk of ADTILI.
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http://dx.doi.org/10.1016/j.ijid.2022.07.071DOI Listing
August 2022

HLA-DRB1∗1502 Is Associated With Anti-N-Methyl-D-aspartate Receptor Encephalitis in Thai Children.

Pediatr Neurol 2022 Jun 26;134:93-99. Epub 2022 Jun 26.

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Electronic address:

Background: Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is one of the most common types of autoimmune encephalitis. Most patients have no apparent immunologic triggers, which suggests a genetic predisposition. This study was conducted to identify human leukocyte antigen (HLA) class II alleles associated with anti-NMDARE in Thai children.

Methods: This case-control study enrolled patients younger than 18 years who were diagnosed with anti-NMDARE between January 2010 and December 2020. A "good outcome" was determined as a patient with a modified Rankin scale score of less than 2 at any follow-up visit. HLA genotypes were determined at four-digit alleles using reverse sequence-specific oligonucleotide probe hybridization. The HLA class II allele frequency in patients was compared with that in a database of 101 healthy control Thai children.

Results: Thirty-four patients were enrolled with a mean age of 12.8 ± 5.6 years (females 85.3%). The HLA-DRB1∗1502 allele frequency was significantly higher in patients than in controls (odds ratio, 2.32; 95% confidence interval, 1.11-4.8, P = 0.023). A good outcome was noted in 14 of 14 (100%) HLA-DRB1∗1502-positive patients (median time to a good outcome, 6 months) and 14 of 17 (82.3%) HLA-DRB1∗1502-negative patients (median time to a good outcome, 3 months). Two (11.8%) HLA-DRB1∗1502-positive patients had one relapse each, and six (35.3%) HLA-DRB1∗1502-negative patients had one to three relapses.

Conclusions: HLA-DRB1∗1502 was significantly associated with anti-NMDARE in our patients. Most patients had good outcomes. HLA-DRB1∗1502-positive patients tended to require a longer time to achieve a good outcome but had less frequent relapses than HLA-DRB1∗1502-negative patients.
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http://dx.doi.org/10.1016/j.pediatrneurol.2022.06.014DOI Listing
June 2022

The Association of and Genotypes and Hepatotoxicity in Thai People Living with HIV.

J Pers Med 2022 Jun 8;12(6). Epub 2022 Jun 8.

Genomic Medicine Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.

Glutathione s-transferase (GST) is a family of drug-metabolizing enzymes responsible for metabolizing and detoxifying drugs and xenobiotic substances. Therefore, deletion polymorphisms of s can be implicated in developing several pathological conditions, including antiretroviral drug-induced liver injury (ARVDILI). Notably, polymorphisms have been shown to be associated with ARVDILI risk. However, data on polymorphisms in the Thai population are limited. Therefore, this study investigated possible associations between genetic polymorphisms and ARVDILI development. A total of 362 people living with HIV (PLHIV) and 85 healthy controls from multiple centers were enrolled. and genetic polymorphisms were determined using polymerase chain reactions. In addition, HLA genotypes were determined using a sequence-based HLA typing method. After comparing genotypic frequencies, there was no significant difference between PLHIV and healthy volunteers. However, while observing the PLHIV group, wild type was significantly associated with a 2.04-fold increased risk of ARVDILI (95%CI: 1.01, 4.14; = 0.045). Interestingly, a combination of wild type and was associated with a 2.28-fold higher risk of ARVDILI (95%CI: 1.15, 4.50; = 0.02). Collectively, wild type and a combination of wild type plus were associated with susceptibility to ARVDILI in the Thai population.
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http://dx.doi.org/10.3390/jpm12060940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225434PMC
June 2022

Global DNA hypomethylation of Alu and LINE-1 transposable elements as an epigenetic biomarker of anti-tuberculosis drug-induced liver injury.

Emerg Microbes Infect 2021 Dec;10(1):1862-1872

Division of Genomic Medicine and Innovation Support, Department of Medical Sciences, Ministry of Public Health, Genomic Medicine Centre, Nonthaburi, Thailand.

Despite being highly effective, anti-tuberculosis (TB) drugs often induce adverse liver injury, anti-TB drug-induced liver injury (ATDILI), leading to treatment failure given no sensitive and selective ATDILI markers. Herein, we conducted a case-control association study to determine whether global DNA methylation of Alu and LINE-1 transposable elements responsible for genomic stability and transcriptional regulation was correlated with clinical parameters indicating ATDILI in TB patients and might serve as an ATDILI biomarker. Alu and LINE-1 methylation levels in blood leukocyte of 130 TB patients (80 ATDILI cases and 50 non-ATDILI cases) and 100 healthy controls were quantified using quantitative combined bisulfite restriction analysis. Both TB patients with and without ATDILI had significantly lower methylation levels of Alu and LINE-1 elements than healthy controls. Compared with non-ATDILI patients, Alu methylation levels were significantly decreased in ATDILI patients, commensurate with LINE-1 methylation analysis. Hypomethylation of Alu and LINE-1 measured within 1-7 days of TB treatment was independently associated with raised levels of serum aminotransferases assessed within 8-60 days of TB treatment. Receiver operating characteristic curve analysis uncovered that Alu and LINE-1 methylation levels were both more sensitive and specific for differentiating ATDILI cases from non-ATDILI cases than serum aminotransferases after starting TB treatment within 1-7 days. Kaplan-Meier analysis displayed a significant association between hypomethylation of Alu and LINE-1 elements and an increased rate of ATDILI occurrence in TB patients. Collectively, global DNA hypomethylation of Alu and LINE-1 elements would reflect ATDILI progression and might serve as novel sensitive and specific ATDILI biomarkers.
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http://dx.doi.org/10.1080/22221751.2021.1976079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451674PMC
December 2021

, , and genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients.

Heliyon 2021 Apr 20;7(4):e06852. Epub 2021 Apr 20.

Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of s polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between s and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of and genes. genotyping data were derived from microarray data. We illustrated that null and / dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, null and / dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, null and / dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082558PMC
April 2021

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm).

Hum Genome Var 2021 Feb 4;8(1). Epub 2021 Feb 4.

University of Patras, School of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualised Therapy, Patras, Greece.

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.
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http://dx.doi.org/10.1038/s41439-021-00135-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862625PMC
February 2021

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations.

Sci Rep 2020 12 4;10(1):21310. Epub 2020 Dec 4.

Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates.

Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in "pharmacogenes". The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.
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http://dx.doi.org/10.1038/s41598-020-78231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718919PMC
December 2020

The Influence of NAT2 Genotypes on Isoniazid Plasma Concentration of Pulmonary Tuberculosis Patients in Southern Thailand.

Tuberc Respir Dis (Seoul) 2020 Dec 3;83(Supple 1):S55-S62. Epub 2020 Nov 3.

Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand.

Background: Isoniazid (INH) is metabolized by polymorphic N-acetyltransferase 2 (NAT2) enzyme, which noticeably alters INH plasma concentration. We aimed to determine the distribution of NAT2 genotype in Thai tuberculosis (TB) patients and correlate their genotype with plasma INH concentrations.

Methods: Blood samples from 55 newly diagnosed pulmonary tuberculosis participants from three hospitals were collected to classify the subject by NAT2 genotype performed by the Multiplex haplotype-specific polymerase chain reaction method. Patients were grouped into three acetylators (fast, intermediate, and slow). On day 14 of tuberculosis treatment, the second blood sample was taken to estimate the peak plasma concentration at 2 hours after oral administration. INH plasma concentration was analyzed by liquid chromatography‒tandem mass spectrometry/mass spectrometry method.

Results: The NAT2 genotype distribution of fast, intermediate, and slow acetylator was 10.9%, 36.4%, and 52.7%, from six, 20, and 29 patients, respectively. The median (interquartile range) of INH plasma concentration at 2 hours post drug administration for these three genotypes were 0.75 (0.69-0.86), 2.56 (2.12-3.97), and 4.25 (3.56-5.50) µg/mL from four, 14, and 12 cases, respectively. The INH plasma concentration at 2 hours after administration was significantly associated with body weight and NAT2 acetylator.

Conclusion: The INH plasma concentration was found lower in fast than intermediate and slow acetylators. Body weight and NAT2 acetylator influenced INH plasma concentrations at 2 hours after drug administration. Therefore, the NAT2 genotype should be known before starting TB treatment to maximize therapeutic outcomes.
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http://dx.doi.org/10.4046/trd.2020.0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837378PMC
December 2020

Association of HLA genotypes with phenytoin induced severe cutaneous adverse drug reactions in Thai children.

Epilepsy Res 2020 05 13;162:106321. Epub 2020 Mar 13.

Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand. Electronic address:

Purpose: Phenytoin (PHT) is a common causative drug for severe cutaneous adverse drug reactions (SCARs) in children. SCARs, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are associated with a variation in HLA genotypes. Blood screening for specific HLA allele before PHT prescription would help in the reduction of the incidence of PHT induced SCARs. This study was to investigate the association between variations of HLA genotypes and PHT induced SCARs in Thai children.

Methods: Cases were Thai children aged between 0-18 years diagnosed with SCARs from PHT. Control groups were Thai children of corresponding age who had taken PHT for a least 12 weeks without any hypersensitivity reaction and healthy population controls. Blood samples from both groups were collected for HLA genotyping using a reverse-sequence specific oligonucleotide (SSO) probes method. Carrier rates of HLA alleles were compared between 22 cases (17 DRESS and 5 SJS-TEN), 60 tolerant controls and 649 population controls.

Results: Two HLA alleles includingHLA-B*51:01 and HLA-C*14:02 were significantly associated with PHT induced DRESS (OR 5.83; 95 % CI 1.36-25.00, p = 0.022 and OR 5.85; 95 % CI 1.16-29.35, p = 0.039). HLA-B*38:02 was significantly associated with PHT induced SJS-TEN (OR12.67; 95 % CI 1.50-106.89, p = 0.044). Haplotype analysis demonstrated the association of HLA haplotype A*11:01-B*51:01-C*14:02 and PHT induced DRESS compared to tolerant controls and the healthy population control group (OR 8.92; 95 % CI 1.47-54.02, p = 0.019, and OR 10.2; 95 % CI 3.04-34.21, p = 0.002). HLA haplotype B*38:02-C*07:01 in PHT induced SJS-TEN was significantly higher than those in tolerant controls and the healthy population control group (40 % vs 3.3 % vs 0.3 %; OR 19.33; 95 % CI 1.98-188.59, p = 0.027 and OR 215.67; 95 % CI 22.40-2076.04, p = 0.0003. HLA-B*15:02 was not associated with PHT induced SCARs.

Significance: An association betweenHLA-B*51:01 and HLA-C*14:02 and PHT induced DRESS and HLA-B*38:02 and PHT induced SJS-TEN has been demonstrated in Thai children.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106321DOI Listing
May 2020

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury.

Sci Rep 2020 03 27;10(1):5628. Epub 2020 Mar 27.

Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand.

Despite being relatively rare, anti-tuberculosis drug-induced liver injury (ATDILI) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for ATDILI. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with ATDILI outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age- and gender-matched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RTL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after anti-tuberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RTL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RTL as a novel indicator for ATDILI progression (AUC = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by anti-tuberculosis agents and might have a potential biomarker for early ATDILI progression.
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http://dx.doi.org/10.1038/s41598-020-62635-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101399PMC
March 2020

and genetic polymorphisms and their association with antituberculosis drug-induced liver injury.

Biomed Rep 2020 Apr 10;12(4):153-162. Epub 2020 Feb 10.

Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.

Antituberculosis (anti-TB) drugs are the most common cause of drug-induced liver injury (DILI). There are numerous studies revealing the associations between the polymorphisms of pharmacogenes and the risk of anti-TB DILI (ATDILI). In the present study, relevant studies regarding the pharmacogenes associated with ATDILI were systematically searched in PubMed and Scopus. A total of 24 genes associated with ATDILI were reported on and the top five reported genes in terms of frequency were revealed to be N-acetyltransferase 2, cytochrome P450 family 2 subfamily E member 1, glutathione S-transferases [glutathione S-transferase mu 1 () and glutathione S-transferase theta 1 ()] and solute carrier organic anion transporter family member 1B1. As ATDILI may be the result of direct and indirect interactions, the encoded proteins were further analysed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to observe the protein-protein interactions and the associations amongst these proteins. The results suggested that only and were central proteins associated with all the other analysed proteins. Therefore, the association between or and the risk of developing ATDILI were further analysed. The results revealed that a deletion genotype was significantly associated with risk of ATDILI [odds ratio (OR), 1.28; 95% confidence interval (CI), 1.08-1.51; P=0.004], whereas the deletion genotype and dual-deletion genotype were not significantly associated with risk of ATDILI. Subgroup analysis based on ethnicity was performed and the results demonstrated a significant association between and ATDILI in South Asian individuals (OR, 1.48; 95% CI, 1.12-1.95; P=0.005), which has not been reported previously, to the best of our knowledge. In conclusion, was associated with ATDILI in South Asian individuals.
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http://dx.doi.org/10.3892/br.2020.1275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054707PMC
April 2020

Southeast Asian Pharmacogenomics Research Network (SEAPharm): Current Status and Perspectives.

Public Health Genomics 2019 4;22(3-4):132-139. Epub 2019 Oct 4.

Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand,

Pharmacogenomics (PGx) is increasingly being recognized as a potential tool for improving the efficacy and safety of drug therapy. Therefore, several efforts have been undertaken globally to facilitate the implementation process of PGx into routine clinical practice. Part of these efforts include the formation of PGx working groups working on PGx research, synthesis, and dissemination of PGx data and creation of PGx implementation strategies. In Asia, the Southeast Asian Pharmacogenomics Research Network (SEAPharm) is established to enable and strengthen PGx research among the various PGx communities within but not limited to countries in SEA; with the ultimate goal to support PGx implementation in the region. From the perspective of SEAPharm member countries, there are several key elements essential for PGx implementation at the national level. They include pharmacovigilance database, PGx research, health economics research, dedicated laboratory to support PGx testing for both research and clinical use, structured PGx education, and supportive national health policy. The status of these essential elements is presented here to provide a broad picture of the readiness for PGx implementation among the SEAPharm member countries, and to strengthen the PGx research network and practice in this region.
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http://dx.doi.org/10.1159/000502916DOI Listing
May 2020

Genomewide Association Study Confirming the Association of with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the -acetyltransferase () region. The A allele of rs1495741, the top SNP in the intergenic region of and (14 kb from ), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57];  = 6.86E-11). This particular SNP was reported as a tag SNP for inferred phenotypes. The AA, AG, and GG genotypes represented slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with acetylator phenotypes. This GWAS shows that is the most important risk factor for ATDILI in the Thai population.
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http://dx.doi.org/10.1128/AAC.02692-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658740PMC
August 2019

Association of HLA genotypes with Beta-lactam antibiotic hypersensitivity in children.

Asian Pac J Allergy Immunol 2021 Sep;39(3):197-205

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 10400.

Background: Beta-lactam (BL) antibiotics hypersensitivity is common in children. Clinical manifestation of BL hypersensitivity varies from mild to severe cutaneous adverse drug reactions (SCARs).

Objective: To determine the association of HLA genotype and BL hypersensitivity and the prevalence of true drug allergy in patients with history of BL hypersensitivity.

Methods: A case-control study was performed in 117 children with aged 1-18 years. Children with history of non-SCARs BL hypersensitivity were evaluated for true drug hypersensitivity including skin test and drug provocation test. Tolerant control patients were children who could tolerate BL for at least 7 days without hypersensitivity reaction. HLA genotype (HLA-A, HLA-B, HLA-C and HLA-DRB1) were performed in 24 cases and 93 tolerant controls using PCR-SSO (polymerase chain reaction - sequence specific oligonucleotide probes).

Results: There were association of HLA-C*04:06 (OR = 13.14, 95%CI: 1.3-137.71; p = 0.027), and HLA-C*08:01 (OR = 4.83, 95%CI: 1.93-16.70; p = 0.016) with BL hypersensitivity. HLA-B*48:01 was strongly associated with immediate reaction from BL hypersensitivity (OR = 37.4, 95%CI: 1.69-824.59; p = 0.016) while HLA-C*04:06, HLA-C*08:01 and HLA-DRB1*04:06 were associated with delayed reaction (p < 0.05). Among 71 cases who were newly evaluated for BL hypersensitivity, only 7 cases (9.8%) had true BL hypersensitivity.

Conclusions: Less than 10% of children with suspected of BL hypersensitivity have true hypersensitivity. There might be a role of HLA-B, HLA-C and HLA-DRB1 genotype in predicting BL hypersensitivity in Thai children.
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http://dx.doi.org/10.12932/AP-271118-0449DOI Listing
September 2021

NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis.

Pharmacogenet Genomics 2018 07;28(7):167-176

Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo.

Background: NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group.

Objective: We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI.

Materials And Methods: Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods.

Results: The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96-2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30-5.63; P=1.76E-08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20-3.57; P=5.73E-18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B).

Conclusion: This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.
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http://dx.doi.org/10.1097/FPC.0000000000000339DOI Listing
July 2018

Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis.

J Hum Genet 2017 Dec 7;62(12):1015-1022. Epub 2017 Sep 7.

Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.

Tuberculosis (TB) is known to be affected by host genetic factors. We reported a specific genetic risk factor through a genome-wide association study (GWAS) that focused on young age onset TB. In this study, we further focused on the heterogeneity of Mycobacterium tuberculosis (M. tb) lineages and assessed its possible interaction with age at onset on host genetic factors. We identified the pathogen lineage in 686 Thai TB cases and GWAS stratified by both infected pathogen lineage information and age at onset revealed a genome-wide significant association of one single-nucleotide polymorphism (SNP) on chromosome 1p13, which was specifically associated with non-Beijing lineage-infected old age onset cases (P=2.54E-08, OR=1.74 (95% CI=1.43-2.12)), when we compared them to the population-matched healthy controls. This SNP locates near the CD53 gene, which encodes a leukocyte surface glycoprotein. Interestingly, the expression of CD53 was also correlated with the patients' active TB status. This is the first report of a pathogen lineage-based genome-wide association study. The results suggested that host genetic risk in TB is depended upon the pathogen genetic background and demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB.
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http://dx.doi.org/10.1038/jhg.2017.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709719PMC
December 2017

Genome-wide association study of neovascular age-related macular degeneration in the Thai population.

J Hum Genet 2017 Nov 13;62(11):957-962. Epub 2017 Jul 13.

Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.

We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10), HTRA1 rs11200638 (P=5.47 × 10) and complement factor H gene (CFH) rs800292 (P=2.53 × 10) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population.
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http://dx.doi.org/10.1038/jhg.2017.72DOI Listing
November 2017

Association of HLA genotypes with phenobarbital hypersensitivity in children.

Epilepsia 2016 Oct 24;57(10):1610-1616. Epub 2016 Aug 24.

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Objective: Phenobarbital hypersensitivity is one of the common drug hypersensitivity syndromes in children. Clinical symptoms of phenobarbital hypersensitivity vary from maculopapular rashes (MPs) to severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug hypersensitivity has been demonstrated to be associated with variations in the HLA genotypes. This study was to investigate the association between the variations of HLA genotypes and phenobarbital hypersensitivity in Thai children.

Methods: The cases were Thai children, between 0 and 18 years of age, who were diagnosed with phenobarbital hypersensitivity, which included SCARs and MPs. The control patients were Thai children of a corresponding age who had taken phenobarbital for at least 12 weeks without any hypersensitivity reaction. Blood samples were collected for HLA genotyping by using a reverse-sequence-specific oligonucleotide (SSO) probes method. The carrier rates of HLA alleles were compared between 47 cases (27 SCARs and 20 MPs) and 54 controls.

Results: The carrier rates of HLA-A*01:01 and HLA-B*13:01 were significantly higher in the phenobarbital-induced SCARs than in the tolerant controls (18.5% vs. 1.85%, p = 0.01, odds ratio [OR] 11.66, 95% confidence interval [CI] 1.21-578.19; 37.04% vs. 11.11%, p = 0.009, OR 4.60, 95%CI 1.29-17.98). There was a trend of a higher carrier rate of HLA-C*06:02 in the phenobarbital-induced SCARs when compared with those in the tolerant controls (29.63% vs. 11.11%, p = 0.059, OR 3.31, 95% CI 0.88-13.31). In contrast to the phenobarbital-induced SCARs, only the HLA-A*01:01 carrier rate in the phenobarbital-induced MPs was significantly higher than those in the tolerant controls (20% vs. 1.85%, p = 0.017, OR 12.69, 95% CI 1.15-661.62).

Significance: An association between phenobarbital hypersensitivity and HLA-A*01:01 and HLA-B*13:01 has been demonstrated in Thai children.
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http://dx.doi.org/10.1111/epi.13509DOI Listing
October 2016

Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis.

Hum Genome Var 2016 4;3:15067. Epub 2016 Feb 4.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.

Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (⩾45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases.
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http://dx.doi.org/10.1038/hgv.2015.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760120PMC
April 2016

CAG-Expansion Haplotype Analysis in a Population with a Low Prevalence of Huntington's Disease.

J Clin Neurol 2014 Jan 6;10(1):32-6. Epub 2014 Jan 6.

Department of Medical Sciences, Medical Genetic Section, National Institute of Health, Ministry of Public Health, Nonthaburi, Thailand.

Background And Purpose: The prevalence of Huntington's disease (HD) among East Asians is less than one-tenth of that among Caucasians. Such a low prevalence may be attributable to a lack of carriers of specific predisposing haplogroups associated with the high instability of the Huntingtin gene (HTT). The aim of this study was to evaluate the association between specific HTT haplogroups and the occurrence of HD in a Thai population.

Methods: CAG-repeat sizes and HTT haplotypes were analyzed in 18 Thai HD patients and 215 control subjects. Twenty-two tagging single-nucleotide polymorphisms (tSNPs) were genotyped.

Results: Only 18 patients from 15 unrelated families were identified over the last 17 years. Pathological CAG-repeat alleles ranged from 39 to 48 repeats (43.5±3.0, mean±SD), and normal alleles ranged from 9 to 24 repeats (16.49±1.74). Only two of the chromosomes studied comprised intermediate alleles. Unlike the Caucasian data, all but 1 of the 22 tSNPs were not associated with the occurrence of HD. The predisposing haplogroups for Caucasian HD (haplogroups A1 and A2) are very rare in Thai patients (<4%). Both HD and normal chromosomes are commonly haplogroups A5 and C, in contrast to the case for Chinese and Japanese patients, in whom only haplogroup C was common in HD chromosomes. The frequency of CAG-repeat sizes of haplogroup A5 and C were also similarly distributed.

Conclusions: HD chromosomes of Thai patients may arise randomly from each haplogroup, with a similar mutation rate. This rate is much lower than the CAG expansions from Caucasian HD haplogroups. These data suggest that the different mechanisms underlie CAG expansion in Thai and Caucasian patients.
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http://dx.doi.org/10.3988/jcn.2014.10.1.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896646PMC
January 2014

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis.

J Hum Genet 2012 Jun 3;57(6):363-7. Epub 2012 May 3.

Medical Genetics Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.

Tuberculosis (TB) is one of the most devastating chronic infectious diseases, but the role of host genetics in disease development after infection in this disease remains unidentified. Genome-wide association studies (GWASs) in Thais and Japanese were carried out and separately analyzed, attempted replication, then, combined by meta-analysis were not yielding any convincing association evidences; these results suggested that moderate to high effect-size genetic risks are not existed for TB per se. Because of failure in replication attempt of the top 50 single-nucleotide polymorphisms (SNPs) identified form meta-analysis data, we empirically split TB cases into young TB case/control data sets (GWAS-T(young)=137/295 and GWAS-J(young)=60/249) and old TB case/control data sets (GWAS-T(old)=300/295 and GWAS-J(old)=123/685), re-analyzed GWAS based on age-stratified data and replicated the significant findings in two independent replication samples (young TB; Rep-T(young)=155/249, Rep-J(young)=41/462 and old TB; Rep-T(old)=212/187, Rep-J(old)=71/619). GWAS and replication studies conducted in young TB identified at-risk locus in 20q12. Although the locus is located in inter-genic region, the nearest genes (HSPEP1-MAFB) from this locus are promising candidates for TB susceptibility. This locus was also associated with anti-TNF responsiveness, drug with increased susceptibility for TB. Moreover, eight SNPs in an old TB meta-analysis and six SNPs in young TB meta-analysis provided replication evidences but did not survive genome-wide significance.These findings suggest that host genetic risks for TB are affected by age at onset of TB, and this approach may accelerate the identification of the major host factors that affect TB in human populations.
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http://dx.doi.org/10.1038/jhg.2012.35DOI Listing
June 2012

Molecular epidemiology of leprosy based on VNTR typing in Thailand.

Lepr Rev 2009 Sep;80(3):280-9

Mycobacterial Laboratory, National Institute of Health, Ministry of Public Health, Thailand.

Recently about 500 new cases of leprosy have been reported each year in Thailand. In addition to a steady rate of new case detection, Thailand is in Southeast Asia where leprosy is endemic in neighbouring countries; therefore, strain differentiation could be useful in tracing origins and routes of infection, and general leprosy surveillance. To identify suitable markers for differentiation of M. leprae strains in different global geographic regions and to determine the applicability of a systematic genotyping method for tracing leprosy transmission, variable nucleotide tandem repeats (VNTRs) of 14 loci were evaluated using DNA extracts from a total of 97 skin biopsies and slit skin smear samples. The alleles per locus ranged from 2-26 providing adequate strain differentiation. Microsatellite loci (GAA)21, (AT)17 are highly polymorphic followed by (GTA)9, (AC)8a, (AC)8b, and (AC)9. The minisatellites 6-7, 21-3 and 27-5 exhibited a limited number of alleles. The repeat of 23-3 showed no polymorphism. Overall, the strain types can be divided into two distinct Thai groups, according to the alleles at the (GGT)5 and 21-3 loci. However, there are no obvious geographical patterns of distribution of VNTR strain types. Closely matched VNTR profiles found in household members of two multi-case families suggested infection through a common source.
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September 2009

A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians.

Nat Genet 2009 May 6;41(5):591-5. Epub 2009 Apr 6.

Human Genome Center, Institute of Medical Science, the University of Tokyo, Japan.

Chronic hepatitis B is a serious infectious liver disease that often progresses to liver cirrhosis and hepatocellular carcinoma; however, clinical outcomes after viral exposure vary enormously among individuals. Through a two-stage genome-wide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, we identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1. We validated these associations by genotyping two SNPs from the region in three additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x 10(-38), OR = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1(*)0202-DPB1(*)0501 and HLA-DPA1(*)0202-DPB1(*)0301, OR = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1(*)0103-DPB1(*)0402 and HLA-DPA1(*)0103-DPB1(*)0401, OR = 0.52 and 0.57, respectively). Our findings show that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus.
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http://dx.doi.org/10.1038/ng.348DOI Listing
May 2009

T-cell recognition of peptides from the Mycobacterium leprae 35 kDa protein in Thai leprosy patients, healthy contacts, and non-contacts.

Immunol Lett 2003 Jul;88(1):71-6

Sasakawa Research Building, Raj-Pracha-Samasai Institute, Leprosy Division, Department of Communicable Disease Control, Ministry of Public Health, Nonthaburi, 11000, Thailand.

The objective of the study was to identify Mycobacterium leprae-specific immunogenic peptides for the development of a skin test reagent. Such a reagent is required for the detection of M. leprae infection and possibly for the diagnosis of patients with active leprosy. For this purpose, we analyzed the in vitro responses of human peripheral blood mononuclear cell (PBMCs) to peptides from the 35 kDa protein of M. leprae. This protein is of interest since it has no homologue within the Mycobacterium tuberculosis complex, although it has a homologue in Mycobacterium avium. The subjects enrolled in the study were paucibacillary (PB) and multibacillary (MB) leprosy patients, healthy contacts, and non-contacts. Seventy-three PB and 124 MB leprosy patients were recruited from four leprosy clinics in Thailand. Fifty-seven healthy contacts were household contacts. Twenty non-leprosy contacts had no family history of or exposure to leprosy. PBMCs from individuals were tested for stimulation with 12 overlapping peptides from the M. leprae 35 kDa protein using the lymphocyte proliferation assay. These peptides were located in four areas containing three to six residues which were distinct for the M. leprae product in comparison to that from M. avium. Four peptides (p60-76, p132-151, p206-224 and p267-286), which were the most permissive from each region and recognized by non-contacts with significantly lower frequencies than other subject groups, were identified. From this preliminary result, we conclude that these four peptides were likely to be M. leprae-specific.
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http://dx.doi.org/10.1016/s0165-2478(03)00065-8DOI Listing
July 2003
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