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Genetic epidemiology of pharmacogenetic variants in South East Asian Malays using whole-genome sequences

Sivadas A, Salleh MZ, Teh LK, Scaria V

Pharmacogenomics J, 2017 10;17(5):461-470.
PMID: 27241059 DOI: 10.1038/tpj.2016.39

Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals. We investigated the allelic diversity of potentially deleterious pharmacogenomic variants in SEA Malay population. Our analysis revealed 227 common and 466 rare potentially functional single nucleotide variants (SNVs) in 437 pharmacogenomic genes involved in drug metabolism, transport and target genes, including 74 novel variants. This study has created one of the most comprehensive maps of pharmacogenetic markers in any population from whole genomes and will hugely benefit pharmacogenomic investigations and drug dosage recommendations in SEA Malays.

Matched MeSH terms: Pharmacogenomic Variants*
Fulltext Incidental pharmacogenetics findings in an HLA-related research: Considerations for primary prevention

Bakhtiar MF, Too CL, Tang MM, Sulaiman S, Tan LK, Ahmad-Fauzi NA, et al.

Clin Exp Allergy, 2019 04;49(4):537-540.
PMID: 30693574 DOI: 10.1111/cea.13347
Matched MeSH terms: Pharmacogenomic Variants*
Systematic characterization and comparison of the CYP2C9 variability of the Orang Asli in Malaysia with 12 populations

Teh LK, Subramaniam V, Tuan Abdu Aziz TA, Lee LS, Ismail MI, Yu CY, et al.

Drug Metab. Pharmacokinet., 2016 Aug;31(4):304-13.
PMID: 27325019 DOI: 10.1016/j.dmpk.2016.04.004

We conducted a systematic characterization of CYP2C9 variants in 61 Orang Asli and 96 Singaporean Malays using the whole genome sequences data and compared the variants with the other 11 HapMap populations. The frequency of rs1057910 (CYP2C9*3) is the highest in the Orang Asli compared to other populations. Three alleles with clinical implication were detected in the Orang Asli while 2 were found in the Singaporean Malays. Large numbers of the Orang Asli are predicted to have reduced metabolic capacity and therefore they would require a lower dose of drugs which are metabolized by CYP2C9. They are also at increased risks of adverse effects and therapeutic failures. A large number of CYP2C9 variants in the Orang Asli were not in the Hardy Weinberg Equilibrium which could be due to small sample size or mutations that disrupt the equilibrium of allele frequencies. In conclusion, different polymorphism patterns, allele frequencies, genotype frequencies and LD blocks are observed between the Orang Asli, the Singaporean Malays and the other populations. The study provided new information on the genetic polymorphism of CYP2C9 which is important for the implementation of precision medicine for the Orang Asli.

Matched MeSH terms: Pharmacogenomic Variants
Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population

Chang CC, Ng CC, Too CL, Choon SE, Lee CK, Chung WH, et al.

Pharmacogenomics J, 2017 03;17(2):170-173.
PMID: 26927288 DOI: 10.1038/tpj.2016.10

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Matched MeSH terms: Pharmacogenomic Variants*
Fulltext Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies: an exploratory pharmacogenetics study

Daud ANA, Bergman JEH, Kerstjens-Frederikse WS, van der Vlies P, Hak E, Berger RMF, et al.

Pharmacogenomics, 2017 Jul;18(10):987-1001.
PMID: 28639488 DOI: 10.2217/pgs-2017-0036

AIM: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors.
METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.
RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.
CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation.

Matched MeSH terms: Pharmacogenomic Variants*
Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation

Loganadan NK, Huri HZ, Vethakkan SR, Hussein Z

Pharmacogenomics J, 2016 06;16(3):209-19.
PMID: 26810132 DOI: 10.1038/tpj.2015.95

The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.

Matched MeSH terms: Pharmacogenomic Variants*
Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients

Makhtar SM, Husin A, Baba AA, Ankathil R

J Genet, 2017 Sep;96(4):633-639.
PMID: 28947711

The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.

Matched MeSH terms: Pharmacogenomic Variants*
Fulltext The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD)

Akkaif MA, Daud NAA, Sha'aban A, Ng ML, Abdul Kader MAS, Noor DAM, et al.

Molecules, 2021 Apr 01;26(7).
PMID: 33915807 DOI: 10.3390/molecules26071987

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2-81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia.

Matched MeSH terms: Pharmacogenomic Variants*
Pharmacometabolomics analysis of plasma to phenotype clopidogrel high on treatment platelets reactivity in coronary artery disease patients

Amin AM, Sheau Chin L, Teh CH, Mostafa H, Mohamed Noor DA, Abdul Kader MASK, et al.

Eur J Pharm Sci, 2018 May 30;117:351-361.
PMID: 29526765 DOI: 10.1016/j.ejps.2018.03.011

Dual antiplatelet therapy (DAPT) of clopidogrel and aspirin is crucial for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, some patients may endure clopidogrel high on treatment platelets reactivity (HTPR) which may cause thromboembolic events. Clopidogrel HTPR is multifactorial with some genetic and non-genetic factors contributing to it. We aimed to use nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis of plasma to investigate this multifactorial and identify metabolic phenotypes and pathways associated with clopidogrel HTPR. Blood samples were collected from 71 CAD patients planned for interventional angiographic procedure (IAP) before the administration of clopidogrel 600 mg loading dose (LD) and 6 h after the LD. Platelets function testing was done 6 h post-LD using VerifyNow® P2Y12 assay. Pre-dose and post-dose plasma samples were analysed using 1H NMR. Multivariate statistical analysis was used to indicate the discriminating metabolites. Two metabotypes, each with 34 metabolites (pre-dose and post-dose) were associated with clopidogrel HTPR. Pathway analysis of these metabotypes revealed that aminoacyl-tRNA biosynthesis, nitrogen metabolism and glycine-serine-threonine metabolism are the most perturbed metabolic pathways associated with clopidogrel HTPR. Furthermore, the identified biomarkers indicated that clopidogrel HTPR is multifactorial where the metabolic phenotypes of insulin resistance, type two diabetes mellitus, obesity, gut-microbiota and heart failure are associated with it. Pharmacometabolomics analysis of plasma revealed new insights on the implicated metabolic pathways and the predisposing factors of clopidogrel HTPR.

Matched MeSH terms: Pharmacogenomic Variants