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Metabolomics profiling and pathway analysis of human plasma and urine reveal further insights into the multifactorial nature of coronary artery disease

Amin AM, Mostafa H, Arif NH, Abdul Kader MAS, Kah Hay Y

Clin Chim Acta, 2019 Jun;493:112-122.
PMID: 30826371 DOI: 10.1016/j.cca.2019.02.030

BACKGROUND: Coronary artery disease (CAD) claims lives yearly. Nuclear magnetic resonance (1H NMR) metabolomics analysis is efficient in identifying metabolic biomarkers which lend credence to diagnosis. We aimed to identify CAD metabotypes and its implicated pathways using 1H NMR analysis.
METHODS: We analysed plasma and urine samples of 50 stable CAD patients and 50 healthy controls using 1H NMR. Orthogonal partial least square discriminant analysis (OPLS-DA) followed by multivariate logistic regression (MVLR) models were developed to indicate the discriminating metabotypes. Metabolic pathway analysis was performed to identify the implicated pathways.
RESULTS: Both plasma and urine OPLS-DA models had specificity, sensitivity and accuracy of 100%, 96% and 98%, respectively. Plasma MVLR model had specificity, sensitivity, accuracy and AUROC of 92%, 86%, 89% and 0.96, respectively. The MVLR model of urine had specificity, sensitivity, accuracy and AUROC of 90%, 80%, 85% and 0.92, respectively. 35 and 12 metabolites were identified in plasma and urine metabotypes, respectively. Metabolic pathway analysis revealed that urea cycle, aminoacyl-tRNA biosynthesis and synthesis and degradation of ketone bodies pathways were significantly disturbed in plasma, while methylhistidine metabolism and galactose metabolism pathways were significantly disturbed in urine. The enrichment over representation analysis against SNPs-associated-metabolite sets library revealed that 85 SNPs were significantly enriched in plasma metabotype.
CONCLUSIONS: Cardiometabolic diseases, dysbiotic gut-microbiota and genetic variabilities are largely implicated in the pathogenesis of CAD.
Fulltext The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

Amin AM, Sheau Chin L, Azri Mohamed Noor D, Sk Abdul Kader MA, Kah Hay Y, Ibrahim B

Cardiol Res Pract, 2017;2017:8062796.
PMID: 28421156 DOI: 10.1155/2017/8062796

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response. This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome.
Fulltext The CYP2C19(∗)1/(∗)2 Genotype Does Not Adequately Predict Clopidogrel Response in Healthy Malaysian Volunteers

Nasyuhana Sani Y, Sheau Chin L, Luen Hui L, Mohd Redhuan Shah Edwin NE, Teck Hwa G, Serebruany VL, et al.

Cardiol Res Pract, 2013;2013:128795.
PMID: 23431496 DOI: 10.1155/2013/128795

Background. The CYP2C19∗2 allele may be associated with a reduced antiplatelet effect for clopidogrel. Here, we assessed whether CYP2C19∗2 alleles correlate with clopidogrel responsiveness following the administration of clopidogrel in healthy Malaysian volunteers. Methods. Ninety volunteers were genotyped for CYP2C19∗2 and CYP2C19∗3 alleles. Forty-five of 90 volunteers were included in the clopidogrel response studies and triaged into three genotypes, namely, CYP2C19∗1/∗1 (n = 17), CYP2C19∗1/∗2 (n = 21), and CYP2C19∗2/∗2 (n = 7). All subjects received 300 mg of clopidogrel, and platelet reactivity was assessed after a four-hour loading utilizing the VerifyNow-P2Y12 assay. Platelet activity was reported using P2Y12 reaction units (PRUs), and nonresponder status was prespecified at PRU ≥ 230. Results. Following clopidogrel intake, CYP2C19∗2/∗2 carriers had a significantly higher mean PRU compared to the CYP2C19∗1/∗2 and CYP2C19∗1/∗1 (291.0 ± 62.1 versus 232.5 ± 81.4 versus 147.4 ± 87.2 PRU, P < 0.001) carriers. Almost half of the participants (46.7%) were found to be nonresponders (3 were CYP2C19∗1/∗1, 11 were CYP2C19∗1/∗2, and 7 were CYP2C19∗2/∗2). Conclusion. In healthy Malaysian volunteers, CYP2C19∗2 allele was associated with a decrease in platelet responsiveness to clopidogrel. However, clopidogrel nonresponders can be found not only in the carriers of CYP2C19∗2/∗2, but also in the carriers of CYP2C19∗1/∗2 and CYP2C19∗1/∗1. The present paper demonstrated that genotype information does not correlate with clopidogrel response, and genotyping may represent a less robust approach compared to platelet activity testing in guiding clopidogrel therapy.
Fulltext Effects of vitamin E on stroke: a systematic review with meta-analysis and trial sequential analysis

Loh HC, Lim R, Lee KW, Ooi CY, Chuan DR, Looi I, et al.

Stroke Vasc Neurol, 2021 Mar;6(1):109-120.
PMID: 33109618 DOI: 10.1136/svn-2020-000519

There are several previous studies on the association of vitamin E with prevention of stroke but the findings remain controversial. We have conducted a systematic review, meta-analysis together with trial sequential analysis of randomised controlled trials to evaluate the effect of vitamin E supplementation versus placebo/no vitamin E on the risk reduction of total, fatal, non-fatal, haemorrhagic and ischaemic stroke. Relevant studies were identified by searching online databases through Medline, PubMed and Cochrane Central Register of Controlled Trials. A total of 18 studies with 148 016 participants were included in the analysis. There was no significant difference in the prevention of total stroke (RR (relative risk)=0.98, 95% CI 0.92-1.04, p=0.57), fatal stroke (RR=0.96, 95% CI 0.77-1.20, p=0.73) and non-fatal stroke (RR=0.96, 95% CI 0.88-1.05, p=0.35). Subgroup analyses were performed under each category (total stroke, fatal stroke and non-fatal stroke) and included the following subgroups (types of prevention, source and dosage of vitamin E and vitamin E alone vs control). The findings in all subgroup analyses were statistically insignificant. In stroke subtypes analysis, vitamin E showed significant risk reduction in ischaemic stroke (RR=0.92, 95% CI 0.85-0.99, p=0.04) but not in haemorrhagic stroke (RR=1.17, 95% CI 0.98-1.39, p=0.08). However, the trial sequential analysis demonstrated that more studies were needed to control random errors. Limitations of this study include the following: trials design may not have provided sufficient power to detect a change in stroke outcomes, participants may have had different lifestyles or health issues, there were a limited number of studies available for subgroup analysis, studies were mostly done in developed countries, and the total sample size for all included studies was insufficient to obtain a meaningful result from meta-analysis. In conclusion, there is still a lack of statistically significant evidence of the effects of vitamin E on the risk reduction of stroke. Nevertheless, vitamin E may offer some benefits in the prevention of ischaemic stroke and additional well-designed randomised controlled trials are needed to arrive at a definitive finding. PROSPERO registration number: CRD42020167827.
1H NMR based pharmacometabolomics analysis of urine identifies metabolic phenotype of clopidogrel high on treatment platelets reactivity in coronary artery disease patients

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

J Pharm Biomed Anal, 2017 Nov 30;146:135-146.
PMID: 28873361 DOI: 10.1016/j.jpba.2017.08.018

Clopidogrel high on treatment platelets reactivity (HTPR) has burdened achieving optimum therapeutic outcome. Although there are known genetic and non-genetic factors associated with clopidogrel HTPR, which explain in part clopidogrel HTPR, yet, great portion remains unknown, often hindering personalizing antiplatelet therapy. Nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis is useful technique to phenotype drug response. We investigated using 1H NMR analysis to phenotype clopidogrel HTPR in urine. Urine samples were collected from 71 coronary artery disease (CAD) patients who were planned for interventional angiographic procedure prior to taking 600mg clopidogrel loading dose (LD) and 6h post LD. Patients' platelets function testing was assessed with the VerifyNow® P2Y12 assay at 6h after LD. Urine samples were analysed using 1H NMR. Multivariate statistical analysis was used to identify metabolites associated with clopidogrel HTPR. In pre-dose samples, 16 metabolites were associated with clopidogrel HTPR. However, 18 metabolites were associated with clopidogrel HTPR in post-dose samples. The pathway analysis of the identified biomarkers reflected that multifactorial conditions are associated with clopidogrel HTPR. It also revealed the implicated role of gut microbiota in clopidogrel HTPR. Pharmacometabolomics not only discovered novel biomarkers of clopidogrel HTPR but also revealed implicated pathways and conditions.
The effect of CYP2C19 genetic polymorphism and non-genetic factors on clopidogrel platelets inhibition in East Asian coronary artery disease patients

Amin AM, Sheau Chin L, Mohamed Noor DA, Mostafa H, Abdul Kader MASK, Kah Hay Y, et al.

Thromb Res, 2017 10;158:22-24.
PMID: 28802144 DOI: 10.1016/j.thromres.2017.07.032
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.