VKORC1 Pharmacogenetics and Pharmacoproteomics in Patients on Warfarin Anticoagulant Therapy: Transthyretin Precursor as a Potential Biomarker

Subbaiya, Ramasamy; Bai, Jing; Sadrolodabaee, Laleh; Karthik, Govindasamy Muralidharan; Singh, Onkar; Koilan, Subramaniyan; Ching, Chi Bun; Chen, Wei Ning; Chowbay, Balram

doi:10.1371/journal.pone.0015064

Cited by 23 publications

(12 citation statements)

References 35 publications

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“…Although there have been significant advances in the understanding of interindividual variability in response to warfarin, it is important to note that at least 40% of the variance in daily dose requirements remains unexplained, and is therefore a limitation of the reductionist approach. Other factors that may influence the response to warfarin such as microRNA and proteomics have been investigated, but further more global approaches that are integrated with the pharmacogenomic determinants are required.…”

Section: Factors Associated With Interindividual Drug Responsementioning

confidence: 99%

Parsing interindividual drug variability: an emerging role for systems pharmacology

Turner

Park

Pirmohamed

2015

WIREs Mechanisms of Disease

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There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype-drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug-specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically-orientated systems biology and pharmacometrics. Pharmacologically-orientated systems biology utilizes high throughput omics technologies, including next-generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data-derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.1302

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Section: Factors Associated With Interindividual Drug Responsementioning

confidence: 99%

Parsing interindividual drug variability: an emerging role for systems pharmacology

Turner

Park

Pirmohamed

2015

WIREs Mechanisms of Disease

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“…Warfarin is an anti-coagulation which is derived from coumarin and widely used in treating thrombosis by reducing the risk of blood clotting( 1 2 3 ), ( Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

The effect of CYP2C92, CYP2C93, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah

et al. 2018

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Polymorphism in the genes encoding CYP2C9 enzyme and VKORC1 reductase significantly influence warfarin dose requirement since patients with CYP2C9*2, CYP2C9*3 and VKORC1 mutant alleles require lower warfarin maintenance doses. Studies have reported the ethnic variations in the frequency of these genes within the various populations in Iran and other parts of the world. However, no such study has been done yet on Kurdish population in Kermanshah. From Kurdish population of Kermanshah province in Iran, a total of 110 patients who had heart surgery and taking warfarin, were genotyped for polymorphisms of VKORC1-1639 G>A, CYP2C9*2, and CYP2C9*3. Polymorphism genotyping was performed by sequencing as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes of MspI, AVAII and KpnI, respectively. The frequencies of VKORC1-1639 GG, GA, and AA genotypes were 42%, 36%, and 22%, respectively and for CYP2C9 1*/1*, 1*/2*, 2*/2*, 1*/3*, 3*/3*, 2*/3* were 71%, 17%, 5.4%, 1.8%, 4.5%, and 0%, respectively. The frequency of VKORC1-1639A allele was 42.3% and the frequencies of CYP2C9*2 and *3 alleles were 14% and 5.4%, respectively. It was indicated that low warfarin dose requirements are strongly associated with the presence of CYP2C9 and VKORC1-1639 variant alleles. Our results confirmed the supply to understand the distribution of genomic biomarkers related to the drugs metabolism for future planning health programs.

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“…128 An iTRAQ based LC-MS/MS pharmacoproteomics approach has also been used to analyze plasma protein profiles of 53 patients with a high (n = 28) and low dose of warfarin therapy (n = 25). 129…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

“…Turning toward pharmaceutical toxicology, iTRAQ measurements of plasma were included with metabolomics methodologies in the study of drug toxicity in relation to the prevention and treatment of thromboembolic conditions . An iTRAQ based LC‐MS/MS pharmacoproteomics approach has also been used to analyze plasma protein profiles of 53 patients with a high ( n = 28) and low dose of warfarin therapy ( n = 25) …”

Section: Applications Of Isobaric Labeling For Serum and Plasma Protementioning

confidence: 99%

Analysis of the plasma proteome using iTRAQ and TMT‐based Isobaric labeling

Moulder

Bhosale

Goodlett

et al. 2017

Mass Spectrometry Reviews

128

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Over the past decade, chemical labeling with isobaric tandem mass tags, such as isobaric tags for relative and absolute quantification reagents (iTRAQ) and tandem mass tag (TMT) reagents, has been employed in a wide range of different clinically orientated serum and plasma proteomics studies. In this review the scope of these works is presented with attention to the areas of research, methods employed and performance limitations. These applications have covered a wide range of diseases, disorders and infections, and have implemented a variety of different preparative and mass spectrometric approaches. In contrast to earlier works, which struggled to quantify more than a few hundred proteins, increasingly these studies have provided deeper insight into the plasma proteome extending the numbers of quantified proteins to over a thousand.

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VKORC1 Pharmacogenetics and Pharmacoproteomics in Patients on Warfarin Anticoagulant Therapy: Transthyretin Precursor as a Potential Biomarker

Cited by 23 publications

References 35 publications

Parsing interindividual drug variability: an emerging role for systems pharmacology

Parsing interindividual drug variability: an emerging role for systems pharmacology

The effect of CYP2C92, CYP2C93, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah

Analysis of the plasma proteome using iTRAQ and TMT‐based Isobaric labeling

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VKORC1 Pharmacogenetics and Pharmacoproteomics in Patients on Warfarin Anticoagulant Therapy: Transthyretin Precursor as a Potential Biomarker

Cited by 23 publications

References 35 publications

Parsing interindividual drug variability: an emerging role for systems pharmacology

Parsing interindividual drug variability: an emerging role for systems pharmacology

The effect of CYP2C9*2, CYP2C9*3, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah

Analysis of the plasma proteome using iTRAQ and TMT‐based Isobaric labeling

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The effect of CYP2C92, CYP2C93, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah