ABSTRACT
Introduction: CYP2C19 plays a major role in the metabolism of various drugs. The most common genetic variants were the CYP2C19*2 and *3 alleles (rs4244285 and rs4986893, non-functional variants). In previous studies, we found that genetic polymorphisms in CYP2C19 variants influenced the active metabolites of clopidogrel and caused major adverse cardiovascular and cerebrovascular effects. However, the distribution of CYP2C19 varies among ethnic groups and according to adverse drug reactions. This study aimed to investigate the frequency of CYP2C19 genetic polymorphisms in the Thai population and analyze the differences in the frequency of CYP2C19 genetic polymorphisms between Thai and other populations. Methods: This study enrolled 211 unrelated healthy Thai individuals in total. We performed a real-time polymerase chain reaction to genotype CYP2C19*2 (681G > A) and CYP2C19*3 (636G > A). Results: In the Thai population, the CYP2C19*1 allele was the most prevalent at 70.14%, while the CYP2C19*2 and *3 alleles were found at frequencies of 25.36% and 4.50%, respectively. Conversely, the CYP2C19*3 allele was not detected in Caucasian, Hispanic, African, Italian, Macedonian, Tanzanian, or North Indian populations. The phenotypic profile of this gene revealed that the frequency of intermediate metabolizers (IMs) is nearly equal to that of extensive metabolizers (EMs), at 42.65% and 48.82% respectively, with genotypes *1/*2 (36.02%) and *1/*3 (6.63%). Likewise, poor metabolizers (PMs) with genotypes *2/*2 (6.16%), *2/*3 (2.37%), and *3/*3 (<1%) are more prevalent in our population as well. Conclusion: The distribution of CYP2C19 genotype and phenotype influenced by non-functional alleles has potential as a pharmacogenomics biomarker for precision medicine and is dependent on an ethnic-specific genetic variation database.
ABSTRACT
Computational methods analyze genomic data to identify genetic variants linked to drug responses, thereby guiding personalized medicine. This study analyzed 942 whole-genome sequences from the Electricity Generating Authority of Thailand (EGAT) cohort to establish a population-specific pharmacogenomic database (TPGxD-1) in the Thai population. Sentieon (version 201808.08) implemented the GATK best workflow practice for variant calling. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0 and employed Stargazer v2.0.2 for star allele analysis. The analysis of 63 very important pharmacogenes (VIPGx) reveals 85,566 variants, including 13,532 novel discoveries. Notably, we identified 464 known PGx variants and 275 clinically relevant novel variants. The phenotypic prediction of 15 VIPGx demonstrated a varied metabolic profile for the Thai population. Genes like CYP2C9 (9%), CYP3A5 (45.2%), CYP2B6 (9.4%), NUDT15 (15%), CYP2D6 (47%) and CYP2C19 (43%) showed a high number of intermediate metabolizers; CYP3A5 (41%), and CYP2C19 (9.9%) showed more poor metabolizers. CYP1A2 (52.7%) and CYP2B6 (7.6%) were found to have a higher number of ultra-metabolizers. The functional prediction of the remaining 10 VIPGx genes reveals a high frequency of decreased functional alleles in SULT1A1 (12%), NAT2 (84%), and G6PD (12%). SLCO1B1 reports 20% poor functional alleles, while PTGIS (42%), SLCO1B1 (4%), and TPMT (5.96%) showed increased functional alleles. This study discovered new variants and alleles in the 63 VIPGx genes among the Thai population, offering insights into advancing clinical pharmacogenomics (PGx). However, further validation is needed using other computational and genotyping methods.
Subject(s)
Pharmacogenetics , Phenotype , Whole Genome Sequencing , Humans , Thailand , Whole Genome Sequencing/methods , Pharmacogenetics/methods , Databases, Genetic , Pharmacogenomic Variants , Male , Female , Alleles , Southeast Asian PeopleABSTRACT
BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.
Subject(s)
Allopurinol , Polymorphism, Single Nucleotide , Humans , Allopurinol/adverse effects , Male , Female , Thailand , Middle Aged , Case-Control Studies , Aged , Adult , Pharmacogenetics , HLA-B Antigens/genetics , Genetic Predisposition to Disease , Pharmacogenomic Variants , Southeast Asian PeopleABSTRACT
Objective: This study aimed to investigate the clinical impact of HLA-B*15:02 pharmacogenomics (PGx) testing before carbamazepine (CBZ)/oxcarbazepine (OXC) prescriptions and to determine whether this PGx testing was associated with the reduction of CBZ/OXC-induced cutaneous adverse drug reactions (CADRs) in Thailand. Methods: This retrospective observational cohort study was conducted by obtaining relevant HLA-B*15:02 PGx-testing and clinical data from electronic medical records during 2011-2020. 384 patient data were included in this study to investigate the clinical decision on CBZ/OXC usage before and after the HLA-B*15:02 PGx testing, and 1,539 patient data were included in this study to demonstrate the incidence of CBZ/OXC-induced SCARs and SJS between HLA-B*15:02 tested and non-tested patients. To analyze and summarize the results, descriptive statistics were employed, and Fisher exact test was used to compare the clinical difference between the HLA-B*15:02 positive and negative groups and to compare the differences of SCARs incidence. Results: 384 patients were included in this study as per the inclusion criteria. Of these, 70 patients carried HLA-B*15:02, of which 63 and 65 patients were not prescribed with CBZ/OXC before and after the availability of genotyping results, respectively. In the remaining HLA-B*15:02 non-carriers, 48, and 189 patients were prescribed CBZ/OXC before and after genotyping results were available, respectively. The findings of this study showed that the incidence of SCARs of CBZ/OXC was significantly lower (p < 0.001) in the HLA-B*15:02 screening arm than in the non-screening arm. Conclusion: HLA-B pharmacogenetics testing influenced the selection of appropriate AEDs. The presence of mild rash in the HLA-B*15:02 negative group indicates that other genetic biomarker (HLA-A*31:01) and/or non-genetic variables are involved in CBZ/OXC-induced CADRs, emphasizing that CBZ/OXC prescriptions necessitate CADR monitoring. The hospital policy and clinical decision support (CDS) alert system is essential to overcome the barriers associated with the utilization of PGx guidelines into clinical practice.
ABSTRACT
SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different populations, and the successful implementation of pharmacogenomics in Thailand for the prevention of SCARs.
ABSTRACT
Background: The HLA-B is the most polymorphic gene, play a crucial role in drug-induced hypersensitivity reactions. There is a lot of evidence associating several risk alleles to life-threatening adverse drug reactions, and a few of them have been approved as valid biomarkers for predicting life-threatening hypersensitivity reactions. Objectives: The objective of this present study is to present the progression of HLA-B pharmacogenomics (PGx) testing in the Thai population during a 10-year period, from 2011 to 2020. Methods: This was a retrospective observational cohort study conducted at the Faculty of Medicine Ramathibodi Hospital. Overall, 13,985 eligible patients who were tested for HLA-B risk alleles between periods of 2011-2020 at the study site were included in this study. Results: The HLA PGx testing has been increasing year by year tremendously, 94 HLA-B testing was done in 2011; this has been raised to 2,880 in 2020. Carbamazepine (n = 4,069, 33%), allopurinol (n = 4,675, 38%), and abacavir (n = 3,246, 26%) were the most common drugs for which the HLA-B genotyping was performed. HLA-B*13:01, HLA-B*15:02 and HLA-B*58:01 are highly frequent, HLA-B*51:01 and HLA-B*57:01 are moderately frequent alleles that are being associated with drug induced hypersensitivity. HLA-B*59:01 and HLA-B*38:01 theses alleles are rare but has been reported with drug induced toxicity. Most of the samples were from state hospital (50%), 36% from private clinical laboratories and 14% from private hospitals. Conclusion: According to this study, HLA-B PGx testing is increasing substantially in Thailand year after year. The advancement of research in this field, increased physician awareness of PGx, and government and insurance scheme reimbursement assistance could all be factors. Incorporating PGx data, along with other clinical and non-clinical data, into clinical decision support systems (CDS) and national formularies, on the other hand, would assist prescribers in prioritizing therapy for their patients. This will also aid in the prediction and prevention of serious adverse drug reactions.
ABSTRACT
BACKGROUND: Phenytoin is the most commonly reported aromatic Anti-Epileptic Drug (AED) to cause Cutaneous Adverse Drug Reactions (CADRs). Cutaneous adverse drug reactions may be immune or non-immune mediated. It has been observed that predisposition is multifactorial and that gene mutations alone cannot be the cause. OBJECTIVES: In this study, we investigated the patient, disease, and drug-related risk factors associated with phenytoin-induced cutaneous adverse drug reactions in South Indian epileptic patients. METHODS: This study was conducted as a single-center prospective case-control study over a period of 13 months. The Fisher's exact test and multivariate binary logistic regression analysis were used to test the association of single and multiple variables, respectively. RESULTS: This study comprised 26 patients with phenytoin-induced cutaneous adverse drug reactions (PHT-CARDs) and 32 phenytoin-tolerant controls with a mean age of 40.60±18.15 and 36.21±14.71 years, respectively. Among 26 phenytoin-induced cutaneous adverse drug reactions, 76.92% cases were mild-moderate reactions and 23.07% were severe. The onset latency period of these reactions ranged from 7-42 days. The multivariate analysis showed that multiple AEDs (OR =18.62, 95% CI 4.28-80.87, p=< .001) and comorbidities (OR= 5.98, 95% CI 1.33-26.78, p=.01) are risk factors for PHT-CADRs. PHT-SCARs were shown to be associated with previous allergy history (OR= 31, % CI 2.40-398.8, p=.008). CONCLUSION: The risk factors found to be associated with CARDs in South Indian Epileptic patients are multiple AEDs, comorbidities, and past allergic history. Therefore, physicians and other associated health care professionals should closely monitor the patients when phenytoin is employed.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Epilepsy , Adult , Anticonvulsants/adverse effects , Case-Control Studies , Epilepsy/drug therapy , Humans , Middle Aged , Phenytoin/adverse effects , Risk Factors , Young AdultABSTRACT
Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and CYP2C9*3 with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (CYP2C9*3) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the HLA B*51:01 and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that CYP2C9*3 was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759-84.87, p = 003). In subgroup analysis, CYP2C9*3 and HLA B*55:01 were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138-136.2, p = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125-15.67, p = 0.035), respectively. Pooled data analysis has confirmed the association between HLA B*51:01/PHT-SCARs (OR = 6.273, 95% CI 2.24-16.69, p = <0.001) and HLA B*51:01/PHT-overall CADRs (OR = 2.323, 95% CI 1.22-5.899, p = 0.037). In this study, neither the case nor the control groups had any patients with HLA B*15:02. The risk variables for PHT-SCARs, PHT-overall CADRs, and PHT-MPE were found to be HLA B*51:01, CYP2C9*3, and HLA B*55:01, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size.