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Jokhab S, AlRasheed MM, Bakheet D, AlMomen A, AlAboud N, Kamali F. The impact of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin dose requirement in Saudi patients. Front Pharmacol 2025; 16:1547142. [PMID: 40371326 PMCID: PMC12075942 DOI: 10.3389/fphar.2025.1547142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/18/2025] [Indexed: 05/16/2025] Open
Abstract
Background Limited data are available on factors that affect warfarin dose requirement in Saudi patients. Saudis are among the underrepresented ethnic groups in warfarin pharmacogenetics research. The present study investigated the frequency of CYP2C9*2 and*3, CYP4F2 (G1347A) and VKORC1 -1639G>A genotypes and their impact on warfarin dose requirement in a cohort of Saudi patients requiring anticoagulation therapy. Methods 193 patients on chronic warfarin therapy and with stable anticoagulation took part in the study. Genotyping for VKORC1 1639G>A, CYP4F2 G1347A, CYP2C9*2 430C>T and CYP2C9*3 1075A>C were performed using TaqMan genotyping assays. Analysis of variance was carried out to determine the association between CYP2C9, CYP4F2, and VKORC1 genotype and warfarin dose requirement in two groups based on target INR range. Backward linear regression analysis identified genetic and clinical factors influencing doe requirements. Results Patients with CYP2C9 and VKORC1 polymorphisms required significantly lower warfarin doses compared to wild-type patients. Carriers of two mutant alleles required lower doses than those with one mutant allele. In contrast, CYP4F2 polymorphisms did not influence warfarin dose. Age and genetic variants in CYP2C9 and VKORC1 were negatively correlated with dose requirements, while body surface area (BSA) was positively correlated. Conclusion Saudi patients with polymorphisms in CYP2C9 and VKORC1 required lower warfarin doses than those with the wild-type allele. CYP4F2 polymorphism had no effect on warfarin dose requirement. Integrating patient clinical factors, including age and BSA, and genetic polymorphisms in CYP2C9 and VKORC1 provides the best estimation of factors contributing to warfarin dose in the Saudi patient population.
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Affiliation(s)
- Salha Jokhab
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Maha M. AlRasheed
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Dana Bakheet
- DNA Extraction and Oligo Synthesis Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdulkareem AlMomen
- Medicine-Hematology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Nouf AlAboud
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Farhad Kamali
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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Zou K, Wei D, Xiang B, Yu T, Huang K, Liu S. Application of low-intensity anticoagulation after On-X mechanical aortic valve replacement. J Cardiothorac Surg 2025; 20:49. [PMID: 39780165 PMCID: PMC11715504 DOI: 10.1186/s13019-024-03215-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
OBJECTIVE To explore the safety and efficacy of low-intensity anticoagulation in patients after On-X mechanical aortic valve replacement. METHODS A total of 104 patients undergoing aortic valve replacement in Cardiac Surgery Department of Sichuan Provincial People's Hospital from December 2018 to December 2021 were randomly divided into low-intensity anticoagulant (INR:1.5-2.0) and high-intensity anticoagulant (INR:2.0-2.5) to compare the incidence of adverse events related to postoperative anticoagulation between the two groups. RESULTS Fifty-three patients were included in the low-intensity anticoagulation group (INR 1.5-2.0), and 51 patients were included in the high-intensity group (2.0-2.5). There was no significant difference in baseline data and surgical index between the two groups (P > 0.05); there were statistically significant differences in PT, INR and bleeding events (P < 0.05), but no significant difference in embolic events (P > 0.05). CONCLUSION For patients requiring On-X mechanical aortic valve replacement who have no risk factors for thromboembolism, it is appropriate to control the INR in the target range 1.5-2.0, which can reduce the incidence of bleeding adverse events and significantly improve the quality of life, without increasing the risk of thromboembolic adverse events.
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Affiliation(s)
- Kun Zou
- NHC Key Laboratory of Nuclear Technology Medical Transformation(MIANYANG CENTRAL HOSPITAL), Mianyang, Sichuan Province, 621000, China
| | - Dachuang Wei
- Cardiac Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China
| | - Bo Xiang
- Cardiac Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China
| | - Tao Yu
- Cardiac Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China
| | - Keli Huang
- Cardiac Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China
| | - Shengzhong Liu
- Cardiac Surgery Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China.
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Wu L, Li Z, Xu L, Fan Y, Mao D, Sun H, Zhuang W. Nrf2 Ameliorates Atrial Fibrosis During Antithrombotic Therapy for Atrial Fibrillation by Modulating CYP2C9 Activity. J Cardiovasc Pharmacol 2024; 84:440-450. [PMID: 39150397 PMCID: PMC11446533 DOI: 10.1097/fjc.0000000000001618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
ABSTRACT Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-β1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.
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Affiliation(s)
- Liting Wu
- Medical Laboratory, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Zhumeng Li
- Medical Laboratory, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Lijuan Xu
- Medical Laboratory, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Yingchao Fan
- Medical Laboratory, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Delong Mao
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China; and
| | - Hanxiao Sun
- Department of Blood Transfusion, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenfang Zhuang
- Medical Laboratory, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China
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Oscanoa TJ, Guevara-Fujita ML, Fujita RM, Muñoz-Paredes MY, Acosta O, Romero-Ortuño R. Association between polymorphisms of the VKORC1 and CYP2C9 genes and warfarin maintenance dose in Peruvian patients. Br J Clin Pharmacol 2024; 90:769-775. [PMID: 37940132 DOI: 10.1111/bcp.15958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 10/20/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023] Open
Abstract
AIMS The aim of this study was to investigate the association between VKORC1 and CYP2C9 genes polymorphisms and the maintenance dose of warfarin in Peruvian patients. METHODS An observational study was conducted on outpatients from the Hospital Grau ESSALUD in Lima, Peru. The participants were selected using nonprobabilistic convenience sampling. Inclusion criteria required patients to have been on anticoagulation therapy for >3 months, maintain stable doses of warfarin (consistent dose for at least 3 outpatient visits), and maintain an international normalized ratio within the therapeutic range of 2.5-3.5. DNA samples were obtained from peripheral blood for gene analysis. RESULTS Seventy patients (mean age of 69.6 ± 13.4 years, 45.7% female) were included in the study. The average weekly warfarin dose was 31.6 ± 15.2 mg. The genotypic frequencies of VKORC1 were as follows: 7.1% (95% confidence interval, 2.4-15.9) for AA; 44.3% (32.4-56.7) for GA; and 48.6% (36.4-60.8) for GG. No deviation from the Hardy-Weinberg equilibrium was observed in the variants studied (P = .56). The mean weekly warfarin doses for AA, GA and GG genotypes were 16.5 ± 2.9, 26.5 ± 9.5 and 37.9 ± 17.1 mg, respectively (P < .001). The genotypic frequencies of CYP2C9 were as follows: 82.8% (72.0-90.8) for CC (*1/*1); 4.3% (1.0-12.0) for CT (*1/*2); and 12.9% (6.1-23.0) for TT (*2/*2). We did not find a significant association between the CYP2C9 gene polymorphism and the dose of warfarin. CONCLUSIONS The AA genotype of the VKORC1 gene was associated with a lower maintenance dose of warfarin in Peruvian patients.
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Affiliation(s)
- Teodoro J Oscanoa
- Geriatric Department, Hospital Nacional Guillermo Almenara Irigoyen, ESSALUD, Lima, Peru
- Facultad de Medicina Humana, Universidad de San Martín de Porres, Lima, Peru
- Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - María L Guevara-Fujita
- Centro de Investigación de Genética y Biología Molecular, Universidad de San Martín de Porres, Facultad de Medicina Humana, Lima, Peru
| | - Ricardo M Fujita
- Centro de Investigación de Genética y Biología Molecular, Universidad de San Martín de Porres, Facultad de Medicina Humana, Lima, Peru
| | | | - Oscar Acosta
- Centro de Investigación de Genética y Biología Molecular, Universidad de San Martín de Porres, Facultad de Medicina Humana, Lima, Peru
| | - Román Romero-Ortuño
- Discipline of Medical Gerontology, School of Medicine, Mercer's Institute for Successful Ageing, St James's Hospital, Dublin, Ireland
- Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland
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Samanta A, Sen Sarma M, Yadav R. Budd-Chiari syndrome in children: Challenges and outcome. World J Hepatol 2023; 15:1174-1187. [PMID: 38075006 PMCID: PMC10698347 DOI: 10.4254/wjh.v15.i11.1174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/08/2023] [Accepted: 10/30/2023] [Indexed: 11/24/2023] Open
Abstract
Budd-Chiari syndrome (BCS) is an uncommon disease of the liver, characterised by obstruction of the hepatic venous outflow tract. The etiological spectrum of BCS as well as venous obstruction pattern show wide geographical and demographic variations across the globe. Compared to adults with BCS, children have primary BCS as the predominant etiology, earlier clinical presentation, and hence better treatment outcome. Underlying prothrombotic conditions play a key role in the etiopathogenesis of BCS, though work-up for the same is often unyielding in children. Use of next-generation sequencing in addition to conventional tests for thrombophilia leads to better diagnostic yield. In recent years, advances in radiological endovascular intervention techniques have revolutionized the treatment and outcome of BCS. Various non-invasive markers of fibrosis like liver and splenic stiffness measurement are being increasingly used to assess treatment response. Elastography techniques provide a novel non-invasive tool for measuring liver and splenic stiffness. This article reviews the diagnostic and therapeutic advances and challenges in children with BCS.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India.
| | - Rajanikant Yadav
- Department of Radiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Rachieru C, Luca CT, Văcărescu C, Petrescu L, Cirin L, Cozma D. Future Perspectives to Improve CHA 2DS 2VASc Score: The Role of Left Atrium Remodelling, Inflammation and Genetics in Anticoagulation of Atrial Fibrillation. Clin Interv Aging 2023; 18:1737-1748. [PMID: 37873054 PMCID: PMC10590594 DOI: 10.2147/cia.s427748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/07/2023] [Indexed: 10/25/2023] Open
Abstract
In 10% of ischemic strokes, non-valvular atrial fibrillation (NVAF) is detected retroactively. Milder, or even asymptomatic forms of NVAF have shown high mortality, thrombotic risk, and deterioration of cognitive function. The current guidelines for the diagnosis and treatment of AF contain "grey areas", such as the one related to anticoagulant treatment in men with CHA2DS2-VASc score 1 and women with score 2. Moreover, parameters such as renal function, patient weight or left atrium remodelling are missing from the recommended guidelines scores. Vulnerable categories of patients including the elderly population, high hemorrhagic risk patients or patients with newly diagnosed paroxysmal episodes of atrial high rate at device interrogation are at risk of underestimation of the thrombotic risk. This review presents a systematic exposure of the most important gaps in evaluation of thrombotic and hemorrhagic risk in patients with NVAF. The authors propose new algorithms and risk factors that should be taken into consideration for an accurate thrombotic and hemorrhagic risk estimation, especially in vulnerable categories of patients.
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Affiliation(s)
- Ciprian Rachieru
- Faculty of Medicine, Department of Internal Medicine I, Discipline of Medical Semiology I “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
- Internal Medicine Department, County Emergency Hospital, Timisoara, 300079, Romania
- Center for Advanced Research in Cardiovascular Pathology and Hemostaseology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
| | - Constantin-Tudor Luca
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
- Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
- Research Center of the Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
| | - Cristina Văcărescu
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
- Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
- Research Center of the Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
| | - Lucian Petrescu
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
| | - Liviu Cirin
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
| | - Dragos Cozma
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 300041, Romania
- Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
- Research Center of the Institute of Cardiovascular Diseases Timisoara, Timisoara, 300310, Romania
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Zhao Q, Chen Y, Huang W, Zhou H, Zhang W. Drug-microbiota interactions: an emerging priority for precision medicine. Signal Transduct Target Ther 2023; 8:386. [PMID: 37806986 PMCID: PMC10560686 DOI: 10.1038/s41392-023-01619-w] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 07/20/2023] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
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Affiliation(s)
- Qing Zhao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Yao Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Weihua Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China.
- The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, PR China.
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, PR China.
- Central Laboratory of Hunan Cancer Hospital, Central South University, 283 Tongzipo Road, Changsha, 410013, PR China.
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Mitchell A, Elmasry Y, van Poelgeest E, Welsh TJ. Anticoagulant use in older persons at risk for falls: therapeutic dilemmas-a clinical review. Eur Geriatr Med 2023; 14:683-696. [PMID: 37392359 PMCID: PMC10447288 DOI: 10.1007/s41999-023-00811-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/02/2023] [Indexed: 07/03/2023]
Abstract
PURPOSE The aim of this clinical narrative review was to summarise the existing knowledge on the use of anticoagulants and potential adverse events in older people at risk of falls with a history of atrial fibrillation or venous thromboembolism. The review also offers practical steps prescribers can take when (de-)prescribing anticoagulants to maximise safety. METHODS Literature searches were conducted using PubMed, Embase and Scopus. Additional articles were identified by searching reference lists. RESULTS Anticoagulants are often underused in older people due to concerns about the risk of falls and intracranial haemorrhage. However, evidence suggests that the absolute risk is low and outweighed by the reduction in stroke risk. DOACs are now recommended first line for most patients due to their favourable safety profile. Off-label dose reduction of DOACs is not recommended due to reduced efficacy with limited reduction in bleeding risk. Medication review and falls prevention strategies should be implemented before prescribing anticoagulation. Deprescribing should be considered in severe frailty, limited life expectancy and increased bleeding risk (e.g., cerebral microbleeds). CONCLUSION When considering whether to (de-)prescribe anticoagulants, it is important to consider the risks associated with stopping therapy in addition to potential adverse events. Shared decision-making with the patient and their carers is crucial as patient and prescriber views often differ.
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Affiliation(s)
- Anneka Mitchell
- Research Institute for the Care of Older People (RICE), Bath, UK.
- Pharmacy Department, University Hospitals Plymouth NHS Trust, Plymouth, UK.
- Life Sciences Department, University of Bath, Bath, UK.
| | - Yasmin Elmasry
- Pharmacy Department, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | | | - Tomas J Welsh
- Research Institute for the Care of Older People (RICE), Bath, UK
- Bristol Medical School, University of Bristol, Bristol, UK
- Royal United Hospitals Bath NHS Foundation Trust, Bath, UK
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Sun B, Ma S, Xiao F, Luo J, Liu M, Liu W, Luo Z. Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice. BMC Cardiovasc Disord 2023; 23:279. [PMID: 37254053 PMCID: PMC10230781 DOI: 10.1186/s12872-023-03321-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/25/2023] [Indexed: 06/01/2023] Open
Abstract
AIM The anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range. METHODS We conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR. RESULTS A total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4. CONCLUSION We confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.
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Affiliation(s)
- Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No.139, People's Middle Street, Furong District, Changsha City, 40013, Hunan Porv., China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Siqing Ma
- Department of Pharmacy, Hunan Institute for Tuberculosis Control, Changsha, China
- Department of Pharmacy, Hunan Chest Hospital, Changsha, China
| | - Feiyan Xiao
- Center for Clinical Trial and Research, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianquan Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No.139, People's Middle Street, Furong District, Changsha City, 40013, Hunan Porv., China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Mouze Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No.139, People's Middle Street, Furong District, Changsha City, 40013, Hunan Porv., China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wenhui Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No.139, People's Middle Street, Furong District, Changsha City, 40013, Hunan Porv., China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhiying Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No.139, People's Middle Street, Furong District, Changsha City, 40013, Hunan Porv., China.
- Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Reeves AA, Hopefl R, Deb S. Evaluation of pharmacogenomic evidence for drugs related to ADME genes in CPIC database. Drug Metab Pers Ther 2023; 38:65-78. [PMID: 36257916 DOI: 10.1515/dmpt-2022-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/19/2022] [Indexed: 02/21/2023]
Abstract
OBJECTIVES Clinical Pharmacogenetics Implementation Consortium (CPIC) is a platform that advances the pharmacogenomics (PGx) practice by developing evidence-based guidelines. The purpose of this study was to analyze the CPIC database for ADME related genes and their corresponding drugs, and evidence level for drug-gene pairs; and to determine the presence of these drug-gene pairs in the highest mortality diseases in the United States. METHODS CPIC database was evaluated for drug-gene pairs related to absorption, distribution, metabolism, and excretion (ADME) properties. National Vital Statistics from Centers for Disease Control and Prevention was used to identify the diseases with the highest mortality. CPIC levels are assigned to different drug-gene pairs based on varying levels of evidence as either A, B, C, or D. All drug-gene pairs assigned with A/B, B/C, or C/D mixed levels were excluded from this study. A stepwise exclusion process was followed to determine the prevalence of various ADME drug-gene pairs among phase I/II enzymes or transporters and stratify the drug-gene pairs relevant to different disease conditions most commonly responsible for death in the United States. RESULTS From a total of 442 drug-gene pairs in the CPIC database, after exclusion of 86 drug-gene pairs with levels A/B, B/C, or C/D, and 211 non-ADME related genes, 145 ADME related drug-gene pairs resulted. From the 145 ADME related drug-genes pairs, the following were the distribution of levels: Level A: 43 (30%), Level B: 22 (15%), Level C: 59 (41%), Level D: 21 (14%). The most prevalent ADME gene with CPIC level A classification was cytochrome P450 2C9 (CYP2C9) (26%) and overall, the most prevalent ADME gene in the CPIC database was CYP2D6 (30%). The most prevalent diseases related to the CPIC evidence related drugs were cancer and depression. CONCLUSIONS We found that there is an abundance of ADME related genes in the CPIC database, including in the high mortality disease states of cancer and depression. There is a differential level of pharmacogenomic evidence in drug-gene pairs enlisted in CPIC where levels A and D having the greatest number of drug-gene pairs. CYP2D6 was the most common ADME gene with CPIC evidence for drug-gene pairs. Pharmacogenomic applications of CPIC evidence can be leveraged to individualize patient therapy and lower adverse effect events.
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Affiliation(s)
- Anthony Allen Reeves
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USA
| | - Robert Hopefl
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USA
| | - Subrata Deb
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USA
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11
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Sethi Y, Patel N, Kaka N, Kaiwan O, Kar J, Moinuddin A, Goel A, Chopra H, Cavalu S. Precision Medicine and the future of Cardiovascular Diseases: A Clinically Oriented Comprehensive Review. J Clin Med 2023; 12:1799. [PMID: 36902588 PMCID: PMC10003116 DOI: 10.3390/jcm12051799] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
Cardiac diseases form the lion's share of the global disease burden, owing to the paradigm shift to non-infectious diseases from infectious ones. The prevalence of CVDs has nearly doubled, increasing from 271 million in 1990 to 523 million in 2019. Additionally, the global trend for the years lived with disability has doubled, increasing from 17.7 million to 34.4 million over the same period. The advent of precision medicine in cardiology has ignited new possibilities for individually personalized, integrative, and patient-centric approaches to disease prevention and treatment, incorporating the standard clinical data with advanced "omics". These data help with the phenotypically adjudicated individualization of treatment. The major objective of this review was to compile the evolving clinically relevant tools of precision medicine that can help with the evidence-based precise individualized management of cardiac diseases with the highest DALY. The field of cardiology is evolving to provide targeted therapy, which is crafted as per the "omics", involving genomics, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics, for deep phenotyping. Research for individualizing therapy in heart diseases with the highest DALY has helped identify novel genes, biomarkers, proteins, and technologies to aid early diagnosis and treatment. Precision medicine has helped in targeted management, allowing early diagnosis, timely precise intervention, and exposure to minimal side effects. Despite these great impacts, overcoming the barriers to implementing precision medicine requires addressing the economic, cultural, technical, and socio-political issues. Precision medicine is proposed to be the future of cardiovascular medicine and holds the potential for a more efficient and personalized approach to the management of cardiovascular diseases, contrary to the standardized blanket approach.
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Affiliation(s)
- Yashendra Sethi
- PearResearch, Dehradun 248001, India
- Department of Medicine, Government Doon Medical College, HNB Uttarakhand Medical Education University, Dehradun 248001, India
| | - Neil Patel
- PearResearch, Dehradun 248001, India
- Department of Medicine, GMERS Medical College, Himmatnagar 383001, India
| | - Nirja Kaka
- PearResearch, Dehradun 248001, India
- Department of Medicine, GMERS Medical College, Himmatnagar 383001, India
| | - Oroshay Kaiwan
- PearResearch, Dehradun 248001, India
- Department of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Jill Kar
- PearResearch, Dehradun 248001, India
- Department of Medicine, Lady Hardinge Medical College, New Delhi 110001, India
| | - Arsalan Moinuddin
- Vascular Health Researcher, School of Sports and Exercise, University of Gloucestershire, Cheltenham GL50 4AZ, UK
| | - Ashish Goel
- Department of Medicine, Government Doon Medical College, HNB Uttarakhand Medical Education University, Dehradun 248001, India
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
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Abstract
Advancements in high-throughput sequencing have yielded vast amounts of genomic data, which are studied using genome-wide association study (GWAS)/phenome-wide association study (PheWAS) methods to identify associations between the genotype and phenotype. The associated findings have contributed to pharmacogenomics and improved clinical decision support at the point of care in many healthcare systems. However, the accumulation of genomic data from sequencing and clinical data from electronic health records (EHRs) poses significant challenges for data scientists. Following the rise of artificial intelligence (AI) technology such as machine learning and deep learning, an increasing number of GWAS/PheWAS studies have successfully leveraged this technology to overcome the aforementioned challenges. In this review, we focus on the application of data science and AI technology in three areas, including risk prediction and identification of causal single-nucleotide polymorphisms, EHR-based phenotyping and CRISPR guide RNA design. Additionally, we highlight a few emerging AI technologies, such as transfer learning and multi-view learning, which will or have started to benefit genomic studies.
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Affiliation(s)
- Jing Lin
- NUHS Corporate Office, National University Health System, Singapore
| | - Kee Yuan Ngiam
- NUHS Corporate Office, National University Health System, Singapore,Department of Surgery, National University of Singapore, Singapore,Correspondence: A/Prof Kee Yuan Ngiam, Group Chief Technology Officer, NUHS Corporate Office, National University Health System, 1E Kent Ridge Road, 119228, Singapore. E-mail:
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13
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Biswas M, Jinda P, Sukasem C. Pharmacogenomics in Asians: Differences and similarities with other human populations. Expert Opin Drug Metab Toxicol 2023; 19:27-41. [PMID: 36755439 DOI: 10.1080/17425255.2023.2178895] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 02/07/2023] [Indexed: 02/10/2023]
Abstract
INTRODUCTION Various pharmacogenomic (PGx) variants differ widely in different ethnicities. and clinical outcomes associated with these variants may also be substantially varied. Literature was searched in different databases, i.e. PubMed, ScienceDirect, Web of Science, and PharmGKB, from inception to 30 June 2022 for this review. AREAS COVERED Certain PGx variants were distinctly varied in Asian populations compared to the other human populations, e.g. CYP2C19*2,*3,*17; CYP2C9*2,*3; CYP2D6*4,*5,*10,*41; UGT1A1*6,*28; HLA-B*15:02, HLA-B*15:21, HLA-B*58:01, and HLA-A*31:01. However, certain other variants do not vary greatly between Asian and other ethnicities, e.g. CYP3A5*3; ABCB1, and SLCO1B1*5. As evident in this review, the risk of major adverse cardiovascular events (MACE) was much stronger in Asian patients taking clopidogrel and who inherited the CYP2C19 loss-of-function alleles, e.g. CYP2C19*2 and*3, when compared to the western/Caucasian patients. Additionally, the risk of carbamazepine-induced severe cutaneous adverse drug reactions (SCARs) for the patients inheriting HLA-B*15:02 and HLA-B*15:21 alleles varied significantly between Asian and other ethnicities. In contrast, both Caucasian and Asian patients inheriting the SLCO1B1*5 variant possessed a similar magnitude of muscle toxicity, i.e. myopathy. EXPERT OPINION Asian countries should take measures toward expanding PGx research, as well as initiatives for the purposes of obtaining clinical benefits from this newly evolving and economically viable treatment model.
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Affiliation(s)
- Mohitosh Biswas
- Department of Pharmacy, University of Rajshahi, 6205, Rajshahi, Bangladesh
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 10400, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Ramathibodi Hospital, Somdech Phra Debaratana Medical Center SDMC, 10400, Bangkok, Thailand
| | - Pimonpan Jinda
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 10400, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Ramathibodi Hospital, Somdech Phra Debaratana Medical Center SDMC, 10400, Bangkok, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 10400, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Ramathibodi Hospital, Somdech Phra Debaratana Medical Center SDMC, 10400, Bangkok, Thailand
- Pharmacogenomics and Precision Medicine Clinic, Bumrungrad Genomic Medicine Institute (BGMI), Bumrungrad International Hospital, 10110, Bangkok, Thailand
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, L69 3GL, Liverpool, UK
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14
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Holail J, Mobarak R, Al-Ghamdi B, Aljada A, Fakhoury H. Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients. Drug Metab Pers Ther 2022; 37:353-359. [PMID: 36476275 DOI: 10.1515/dmpt-2022-0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.
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Affiliation(s)
- Jasmine Holail
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Reem Mobarak
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Bandar Al-Ghamdi
- Heart Center, King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Hana Fakhoury
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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15
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de Lara DV, de Melo DO, Kawakami DY, Gonçalves TS, Santos PC. Pharmacogenetic testing-guided treatment for oncology: an overview of reviews. Pharmacogenomics 2022; 23:739-748. [PMID: 36001087 DOI: 10.2217/pgs-2022-0064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Pharmacogenetics is the relationship between an individual's genetic variations and their response to pharmacological treatment. We conducted an overview of reviews on the use of post-treatment pharmacogenetic testing for oncology, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. We selected six eligible systematic reviews. The most studied drug categories were estrogen agonists/antagonists and fluoropyrimidines associated with cytochrome P450 and dihydropyrimidine dehydrogenase genes (CYP2D6 and DPYD), but many studies were classified as being of critically low or low quality. There is a need for more high-quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of pharmacogenetic testing for oncology.
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Affiliation(s)
- Danilo Vieira de Lara
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
| | - Daniela Oliveira de Melo
- Institute of Environmental Sciences, Chemistry & Pharmaceuticals, Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, 09913-030, Brazil
| | - Daniele Y Kawakami
- Institute of Environmental Sciences, Chemistry & Pharmaceuticals, Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, 09913-030, Brazil
| | - Thuane S Gonçalves
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
| | - Paulo Cjl Santos
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
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16
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Wanounou M, Shaul C, Abu Ghosh Z, Alamia S, Caraco Y. The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)-Warfarin. Clin Pharmacol Ther 2022; 112:156-163. [PMID: 35426132 PMCID: PMC9322346 DOI: 10.1002/cpt.2613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/07/2022] [Indexed: 12/21/2022]
Abstract
Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.
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Affiliation(s)
- Maor Wanounou
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.,Faculty of Medicine, Institute of Drug Research, School of Pharmacy, Hebrew University, Jerusalem, Israel
| | - Chanan Shaul
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.,Faculty of Medicine, Institute of Drug Research, School of Pharmacy, Hebrew University, Jerusalem, Israel
| | - Zahi Abu Ghosh
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Shoshana Alamia
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yoseph Caraco
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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17
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Salmasi S, Högg T, Safari A, De Vera MA, Lynd LD, Koehoorn M, Barry AR, Andrade JG, Loewen P. The Random Effects Warfarin Days' Supply (REWarDS) Model: Development and Validation of a Novel Method for Estimating Exposure to Warfarin Using Administrative Data. Am J Epidemiol 2022; 191:1116-1124. [PMID: 35015808 DOI: 10.1093/aje/kwab295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 08/26/2021] [Accepted: 12/23/2021] [Indexed: 11/15/2022] Open
Abstract
Warfarin's complex dosing is a significant barrier to measurement of its exposure in observational studies using population databases. Using population-based administrative data (1996-2019) from British Columbia, Canada, we developed a method based on statistical modeling (Random Effects Warfarin Days' Supply (REWarDS)) that involves fitting a random-effects linear regression model to patients' cumulative dosage over time for estimation of warfarin exposure. Model parameters included a minimal universally available set of variables from prescription records for estimation of patients' individualized average daily doses of warfarin. REWarDS estimates were validated against a reference standard (manual calculation of the daily dose using the free-text administration instructions entered by the dispensing pharmacist) and compared with alternative methods (fixed window, fixed tablet, defined daily dose, and reverse wait time distribution) using Pearson's correlation coefficient (r), the intraclass correlation coefficient, and the root mean squared error. REWarDS-estimated days' supply showed strong correlation and agreement with the reference standard (r = 0.90 (95% confidence interval (CI): 0.90, 0.90); intraclass correlation coefficient = 0.95 (95% CI: 0.94, 0.95); root mean squared error = 8.24 days) and performed better than all of the alternative methods. REWarDS-estimated days' supply was valid and more accurate than estimates from all other available methods. REWarDS is expected to confer optimal precision in studies measuring warfarin exposure using administrative data.
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18
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Asiimwe IG, Pirmohamed M. Ethnic Diversity and Warfarin Pharmacogenomics. Front Pharmacol 2022; 13:866058. [PMID: 35444556 PMCID: PMC9014219 DOI: 10.3389/fphar.2022.866058] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/14/2022] [Indexed: 12/23/2022] Open
Abstract
Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, most of these studies have been conducted in Whites or Asians which means the current pharmacogenomics evidence-base does not reflect ethnic diversity. Due to differences in minor allele frequencies of key genetic variants, studies conducted in Whites/Asians may not be applicable to underrepresented populations such as Blacks, Hispanics/Latinos, American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. This may exacerbate health inequalities when Whites/Asians have better anticoagulation profiles due to the existence of validated pharmacogenomic dosing algorithms which fail to perform similarly in the underrepresented populations. To examine the extent to which individual races/ethnicities are represented in the existing body of pharmacogenomic evidence, we review evidence pertaining to published pharmacogenomic dosing algorithms, including clinical utility studies, cost-effectiveness studies and clinical implementation guidelines that have been published in the warfarin field.
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Affiliation(s)
- Innocent G Asiimwe
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Munir Pirmohamed
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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19
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de Lara DV, de Melo DO, Araújo Silva LC, Gonçalves TS, Júnior Lima Santos PC. Pharmacogenetics of clopidogrel and warfarin in the treatment of cardiovascular diseases: an overview of reviews. Pharmacogenomics 2022; 23:443-452. [PMID: 35380455 DOI: 10.2217/pgs-2021-0158] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Pharmacogenetics (PGx) is the relationship between an individual's genetic variations and the response to pharmacological treatment. We chose to perform an overview of reviews on PGx testing-guided treatment for cardiovascular diseases, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. The most studied gene-drug pairs were clopidogrel and warfarin associated with cytochrome p450 and vitamin K epoxide reductase complex subunit 1 genes (CYP2C19, CYP2C9 and VKORC1), classified as critically low quality. There is a need for more quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of PGx testing for cardiovascular diseases.
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Affiliation(s)
- Danilo Vieira de Lara
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
| | - Daniela Oliveira de Melo
- Department of Pharmaceutical Sciences, Institute of Environmental Sciences, Chemistry & Pharmaceuticals, Universidade Federal de São Paulo, Diadema, São Paulo, 09913-030, Brazil
| | - Lucas Caetano Araújo Silva
- Department of Pharmaceutical Sciences, Institute of Environmental Sciences, Chemistry & Pharmaceuticals, Universidade Federal de São Paulo, Diadema, São Paulo, 09913-030, Brazil
| | - Thuane Sales Gonçalves
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
| | - Paulo Caleb Júnior Lima Santos
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM - Unifesp, São Paulo, 04044-020, Brazil
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20
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Holail J, Mobarak R, Al-Ghamdi B, Aljada A, Fakhoury H. Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients. Drug Metab Pers Ther 2022; 0:dmdi-2022-0108. [PMID: 35365981 DOI: 10.1515/dmdi-2022-0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/14/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.
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Affiliation(s)
- Jasmine Holail
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Reem Mobarak
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Bandar Al-Ghamdi
- Heart Center, King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Hana Fakhoury
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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21
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Biswas M, Sawajan N, Rungrotmongkol T, Sanachai K, Ershadian M, Sukasem C. Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies. Front Pharmacol 2022; 13:835136. [PMID: 35250581 PMCID: PMC8894812 DOI: 10.3389/fphar.2022.835136] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/24/2022] [Indexed: 01/18/2023] Open
Abstract
Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug-gene pairs (atazanavir-UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz-CYP2B6; nevirapine-HLA, CYP2B6, ABCB1; lopinavir-SLCO1B3, ABCC2; ribavirin-SLC28A2; tocilizumab-FCGR3A; ivermectin-ABCB1; oseltamivir-CES1, ABCB1; clopidogrel-CYP2C19, ABCB1, warfarin-CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)-CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug-drug interactions (DDIs) and drug-herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug-gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.
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Affiliation(s)
- Mohitosh Biswas
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Nares Sawajan
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Department of Pathology, School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
| | - Thanyada Rungrotmongkol
- Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Kamonpan Sanachai
- Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Maliheh Ershadian
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Pharmacogenomics and Precision Medicine, The Preventive Genomics and Family Check-up Services Center, Bumrungrad International Hospital, Bangkok, Thailand
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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22
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Colet C, Amador TA, Castro S, Figueras A, Heineck I. Bleeding associated with self-medication in warfarin users: A prospective observational study in Ijuí (Brazil). BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
| | | | - Stela Castro
- Universidade Federal do Rio Grande do Sul, Brazil
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Leopold JA. Personalizing treatments for patients based on cardiovascular phenotyping. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2022; 7:4-16. [PMID: 36778892 PMCID: PMC9913616 DOI: 10.1080/23808993.2022.2028548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Introduction Cardiovascular disease persists as the leading cause of death worldwide despite continued advances in diagnostics and therapeutics. Our current approach to patients with cardiovascular disease is rooted in reductionism, which presupposes that all patients share a similar phenotype and will respond the same to therapy; however, this is unlikely as cardiovascular diseases exhibit complex heterogeneous phenotypes. Areas covered With the advent of high-throughput platforms for omics testing, phenotyping cardiovascular diseases has advanced to incorporate large-scale molecular data with classical history, physical examination, and laboratory results. Findings from genomics, proteomics, and metabolomics profiling have been used to define more precise cardiovascular phenotypes and predict adverse outcomes in population-based and disease-specific patient cohorts. These molecular data have also been utilized to inform drug efficacy based on a patient's unique phenotype. Expert opinion Multiscale phenotyping of cardiovascular disease has revealed diversity among patients that can be used to personalize pharmacotherapies and predict outcomes. Nonetheless, precision phenotyping for cardiovascular disease remains a nascent field that has not yet translated into widespread clinical practice despite its many potential advantages for patient care. Future endeavors that demonstrate improved pharmacotherapeutic responses and associated reduction in adverse events will facilitate mainstream adoption of precision cardiovascular phenotyping.
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Affiliation(s)
- Jane A. Leopold
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB0630K, Boston, Massachusetts, USA
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24
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Influence of NQO1 Polymorphisms on Warfarin Maintenance Dose: A Systematic Review and Meta-Analysis (rs1800566 and rs10517). Cardiovasc Ther 2021; 2021:5534946. [PMID: 34457036 PMCID: PMC8376459 DOI: 10.1155/2021/5534946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 07/15/2021] [Accepted: 08/04/2021] [Indexed: 11/17/2022] Open
Abstract
This meta-analysis was conducted to analyze the effect of NQO1 polymorphism on the warfarin maintenance dosage. Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, and the Cochrane Library for eligible studies published prior to July 7, 2021. The required data were extracted, and experts were consulted when necessary. Review Manager Version 5.4 software was used to analyze the relationship between NQO1 polymorphisms and the warfarin maintenance dosage. Four articles involving 757 patients were included in the meta-analysis. Patients who were NQO1 rs10517 G carriers (AG carriers or GG carriers) required a 48% higher warfarin maintenance dose than those who were AA carriers. Patients with NQO1 rs1800566 CT carriers required a 13% higher warfarin dose than those who were CC carriers, with no associations observed with the other comparisons of the NQO1 rs1800566 genotypes. However, the results obtained by comparing the NQO1 rs1800566 genotypes require confirmation, as significant changes in the results were found in sensitivity analyses. Our meta-analysis suggests that the NQO1 rs10517and NQO1 rs1800566 variant statuses affect the required warfarin maintenance dose.
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Sridharan K, Sivaramakrishnan G. A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional. J Clin Pharm Ther 2021; 46:640-648. [PMID: 33346393 DOI: 10.1111/jcpt.13334] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/17/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVES Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. METHODS Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. RESULTS AND DISCUSSION Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. WHAT IS NEW AND CONCLUSION The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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26
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Shukla A, Shreshtha A, Mukund A, Bihari C, Eapen CE, Han G, Deshmukh H, Cua IHY, Lesmana CRA, Al Meshtab M, Kage M, Chaiteeraki R, Treeprasertsuk S, Giri S, Punamiya S, Paradis V, Qi X, Sugawara Y, Abbas Z, Sarin SK. Budd-Chiari syndrome: consensus guidance of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2021; 15:531-567. [PMID: 34240318 DOI: 10.1007/s12072-021-10189-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/11/2021] [Indexed: 02/07/2023]
Abstract
Budd Chiari syndrome (BCS) is a diverse disease with regard to the site of obstruction, the predisposing thrombophilic disorders and clinical presentation across the Asia-Pacific region. The hepatic vein ostial stenosis and short segment thrombosis are common in some parts of Asia-Pacific region, while membranous obstruction of the vena cava is common in some and complete thrombosis of hepatic veins in others. Prevalence of myeloproliferative neoplasms and other thrombophilic disorders in BCS varies from region to region and with different sites of obstruction. This heterogeneity also raises several issues and dilemmas in evaluation and approach to management of a patient with BCS. The opportunity to recanalize hepatic vein in patients with hepatic vein ostial stenosis or inferior vena cava stenting or pasty among those membranous obstruction of the vena cava is a unique opportunity in the Asia-Pacific region to restore hepatic outflow closely mimicking physiology. In order to address these issues arising out of the diversity as well as the unique features in the region, the Asia Pacific Association for Study of Liver has formulated these guidelines for clinicians.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India.
| | | | - Amar Mukund
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chhagan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - C E Eapen
- Christian Medical College, Vellore, India
| | - Guohong Han
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xian, China
| | - Hemant Deshmukh
- Dean and Head of Radiology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Ian Homer Y Cua
- Institute of Digestive and Liver Diseases, St Lukes Medical Center, Global City, Philippines
| | - Cosmas Rinaldi Adithya Lesmana
- Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | - Mamun Al Meshtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
- Center for Innovative Cancer Therapy, Kurume University Research, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Masayoshi Kage
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Roongruedee Chaiteeraki
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Suprabhat Giri
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Sundeep Punamiya
- Vascular and Interventional Radiology, Tan Tock Seng Hospital, Singapore, Singapore
| | - Valerie Paradis
- Dpt dAnatomie Pathologique, Hôpital Beaujon, 100 bd du Gal Leclerc, Clichy, 92110, France
| | - Xingshun Qi
- General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), No. 83 Wenhua Road, Shenyang, China
| | - Yasuhiko Sugawara
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto, Japan
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Dr. Ziauddin University Hospital Clifton, Karachi, Pakistan
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27
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Vuorinen AL, Lehto M, Niemi M, Harno K, Pajula J, van Gils M, Lähteenmäki J. Pharmacogenetics of Anticoagulation and Clinical Events in Warfarin-Treated Patients: A Register-Based Cohort Study with Biobank Data and National Health Registries in Finland. Clin Epidemiol 2021; 13:183-195. [PMID: 33727862 PMCID: PMC7954279 DOI: 10.2147/clep.s289031] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/19/2021] [Indexed: 01/22/2023] Open
Abstract
PURPOSE To assess the association between VKORC1 and CYP2C9 variants and the incidence of adverse drug reactions in warfarin-treated patients in a real-world setting. MATERIALS AND METHODS This was a register-based cohort study (PreMed) linking data from Finnish biobanks, national health registries and patient records between January 1st 2007 and June 30th 2018. The inclusion criteria were: 1) ≥18 years of age, 2) CYP2C9 and VKORC1 genotype information available, 3) a diagnosis of a cardiovascular disease, 4) at least one warfarin purchase, 5) regular INR tests. Eligible individuals were divided into two warfarin sensitivity groups; normal responders, and sensitive and highly sensitive responders based on their VKORC1 and CYP2C9 genotypes. The incidences of clinical events were compared between the groups using Cox regression models. RESULTS The cohort consisted of 2508 participants (45% women, mean age of 69 years), of whom 65% were categorized as normal responders and 35% sensitive or highly sensitive responders. Compared to normal responders, sensitive and highly sensitive responders had fewer INR tests below 2 (median: 33.3% vs 43.8%, 95% CI: -13.3%, -10.0%) and more above 3 (median: 18.2% vs 6.7%, 95% Cl: 8.3%, 10.8%). The incidence (per 100 patient-years) of bleeding outcomes was 5.4 for normal responders and 5.6 for the sensitive and highly sensitive responder group (HR=1.03, 95% CI: 0.74, 1.44). The incidence of thromboembolic outcomes was 4.9 and 7.8, respectively (HR=1.48, 95% CI: 1.08, 2.03). CONCLUSION In a real-world setting, genetically sensitive and highly sensitive responders to warfarin had more high INR tests and required a lower daily dose of warfarin than normal responders. However, the risk for bleeding events was not increased in sensitive and highly sensitive responders. Interestingly, the risk of thromboembolic outcomes was lower in normal responders compared to the sensitive and highly sensitive responders. TRIAL REGISTRATION NCT04001166.
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Affiliation(s)
| | - Mika Lehto
- Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
- University of Helsinki, Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
- Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Kari Harno
- Department of Health and Social Management, University of Eastern Finland, Kuopio, Finland
| | - Juha Pajula
- VTT Technical Research Centre of Finland, Tampere, Finland
| | - Mark van Gils
- VTT Technical Research Centre of Finland, Tampere, Finland
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Abu Ghosh Z, Alamia S, Shaul C, Caraco Y. Comparison of CYP2C9 Activity in Ethiopian and Non-Ethiopian Jews Using Phenytoin as a Probe. Front Pharmacol 2020; 11:566842. [PMID: 33071782 PMCID: PMC7542311 DOI: 10.3389/fphar.2020.566842] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/09/2020] [Indexed: 11/13/2022] Open
Abstract
The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin. Analysis of CYP2C9*2, *3, *5, *6, *8, and *11 was carried by direct sequencing. PMR was significantly correlated with CYP2C9 genotype in both groups (p < 0.002). Mean PMR values were similar among Ethiopians and non-Ethiopians despite the fact that the fraction of non-carriers of CYP2C9 variant alleles was significantly different (85 vs. 53%, respectively, p < 0.001). However, among non-carriers of CYP2C9*2, *3, *5, *6, *8, and *11 variant alleles, PMR24/12 and PMR24/24 values were 30 and 34% greater respectively in the non-Ethiopians group (p < 0.001). In conclusion-CYP2C9 activity as measured by PMR is similar in Ethiopian and non-Ethiopian Jews. However, among non-carriers of CYP2C9 variant alleles accounting for 85% of Ethiopian Jews, CYP2C9 activity is decreased by approximately one third as compared with non-Ethiopian Jews. Unique genetic CYP2C9 polymorphisms occurring only in Ethiopians may account for this difference.
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Affiliation(s)
- Zahi Abu Ghosh
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Shoshana Alamia
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Chanan Shaul
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yoseph Caraco
- Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Asiimwe IG, Zhang EJ, Osanlou R, Krause A, Dillon C, Suarez-Kurtz G, Zhang H, Perini JA, Renta JY, Duconge J, Cavallari LH, Marcatto LR, Beasly MT, Perera MA, Limdi NA, Santos PCJL, Kimmel SE, Lubitz SA, Scott SA, Kawai VK, Jorgensen AL, Pirmohamed M. Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis. Clin Pharmacol Ther 2020; 107:1420-1433. [PMID: 31869433 PMCID: PMC7217737 DOI: 10.1002/cpt.1755] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/05/2019] [Indexed: 12/20/2022]
Abstract
Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.
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Affiliation(s)
- Innocent G. Asiimwe
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool
| | - Eunice J. Zhang
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool
| | - Rostam Osanlou
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool
| | - Amanda Krause
- Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand, Johannesburg, South Africa
| | - Chrisly Dillon
- Department of Neurology & Epidemiology, Hugh Kaul Precision Medicine Institute, The University of Alabama at Birmingham
| | | | - Honghong Zhang
- Department of Pharmacology, Center for Pharmacogenomics, Northwestern University, Chicago IL
| | - Jamila A Perini
- Research Laboratory of Pharmaceutical Sciences, West Zone State University-UEZO, Rio de Janeiro, Brazil
| | - Jessicca Y. Renta
- University of Puerto Rico School of Pharmacy, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067
| | - Jorge Duconge
- University of Puerto Rico School of Pharmacy, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067
| | - Larisa H Cavallari
- Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA
| | - Leiliane R. Marcatto
- Laboratory of Genetics and Molecular Cardiology, Faculdade de Medicina FMUSP, Heart Institute (InCor), Universidade de São Paulo, São Paulo, Brazil
| | - Mark T. Beasly
- Department of Neurology & Epidemiology, Hugh Kaul Precision Medicine Institute, The University of Alabama at Birmingham
| | - Minoli A Perera
- Department of Pharmacology, Center for Pharmacogenomics, Northwestern University, Chicago IL
| | - Nita A. Limdi
- Department of Neurology & Epidemiology, Hugh Kaul Precision Medicine Institute, The University of Alabama at Birmingham
| | - Paulo C. J. L. Santos
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, EPM-Unifesp, São Paulo, Brazil
| | - Stephen E. Kimmel
- Perelman School of Medicine at the University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics
| | - Steven A. Lubitz
- Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
| | - Stuart A. Scott
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Vivian K. Kawai
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Andrea L. Jorgensen
- Department of Biostatistics, Institute of Translational Medicine, University of Liverpool
- These authors contributed equally: Andrea Jorgensen and Munir Pirmohamed
| | - Munir Pirmohamed
- The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool
- These authors contributed equally: Andrea Jorgensen and Munir Pirmohamed
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30
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Shah RR. Genotype‐guided warfarin therapy: Still of only questionable value two decades on. J Clin Pharm Ther 2020; 45:547-560. [DOI: 10.1111/jcpt.13127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 02/07/2020] [Indexed: 12/20/2022]
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Li W, Wang P, Le S, Xi W, Wang J, Yin L, Wang Q, Zhang Y, Wang Z. Benefits may not outweigh risks of low molecular weight heparin (LMWH) in early postoperative thromboprophylaxis following minimally invasive cardiac surgery: a propensity score-matched analysis. J Thorac Dis 2020; 11:5266-5273. [PMID: 32030244 DOI: 10.21037/jtd.2019.11.56] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Whether the benefits of early prophylactic anticoagulation by low molecular weight heparin (LMWH) would outweigh its possible harms in patients after minimally invasive cardiac surgery (MICS) remains contentious. The aims of this study were to define the incidence of venous thromboembolism (VTE) and to assess whether early prophylactic anticoagulation by LMWH postoperatively was indeed effective in reducing VTE without increasing risk of complications after MICS. Methods This investigation was a single-center, retrospective, propensity score-matched analysis study. A total of 473 patients underwent MICS, of whom 257 received prophylactic anticoagulation with LMWH (LMWH group) in the early postoperative period and 216 were not treated with LMWH (Control group). The main outcome measurements included the incidence of embolism events and major bleeding events, the volume of erythrocyte transfusion, the volume of drainage and the duration of drainage after MICS. In addition, the incidence of poor wound healing, the mechanical ventilation time, ICU stay time and postoperative hospitalization time were also documented. Results There were fewer embolic events (P=1.000) and a higher rate of major bleeding events (P=0.008) in the LMWH group than the Control group, and their magnitude and significance were maintained in the propensity matched analysis. In the matched cohorts, there was no significant difference in the total volume of red blood cell transfusion (P=0.552), assisted mechanical ventilation time (P=0.542), and the ICU stay time (P=0.166) between the two groups; while the volume of drainage (P<0.001) and the duration of drainage (P<0.001) in the LMWH group were significantly more than the Control group, and the incidence of poor wound healing (P=0.009) and the postoperative hospitalization time (P<0.001) were significantly increased in the LMWH group. Conclusions Early prophylactic anticoagulation with LMWH could not reduce the incidence of embolism events after MICS. Instead, it might increase postoperative major bleeding events and prolong drainage tube indwelling time and the length of hospital stay.
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Affiliation(s)
- Wei Li
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan 430012, China
| | - Pei Wang
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Shiguan Le
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Surgery, 69220 Hospital of Chinese People's Liberation Army, Kuqa County 842000, China
| | - Wang Xi
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Jing Wang
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Liang Yin
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Qing Wang
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Yufeng Zhang
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Zhinong Wang
- Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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Chinese Patients With Heart Valve Replacement Do Not Benefit From Warfarin Pharmacogenetic Testing on Anticoagulation Outcomes. Ther Drug Monit 2019; 41:748-754. [PMID: 31259883 DOI: 10.1097/ftd.0000000000000664] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry; yet, its utility in Chinese patients with heart valve replacement remains unresolved. METHODS A total of 2264 patients who underwent heart valve replacement at Wuhan Asia Heart Hospital were enrolled in this study. Patients were randomly divided into 2 groups, namely, a genotype-guided and a traditional clinically guided warfarin dosing group. In the genotype-guided group (n = 1134), genotyping for CYP2C9 and VKORC1 (-1639 G→A) was performed using TaqMan genotyping assay. Warfarin doses were predicted with the International Warfarin Pharmacogenetics Consortium algorithm. Patients in the control group (n = 1130) were clinically guided. The primary outcome was to compare the incidence of adverse events (major bleeding and thrombotic) during a 90-day follow-up period between 2 groups. Secondary objectives were to describe effects of the pharmacogenetic intervention on the first therapeutic-target-achieving time, the stable maintenance dose, and the hospitalization days. RESULTS A total of 2245 patients were included in the analysis. Forty-nine events occurred during follow-up. Genotype-guided dosing strategy did not result in a reduction in major bleeding (0.26% versus 0.63%; hazard ratio, 0.44; 95% confidence interval, 0.13-1.53; P = 0.20) and thrombotic events (0.89% versus 1.61%; hazard ratio, 0.56; 95% confidence interval, 0.27-1.17; P = 0.12) compared with clinical dosing group. Compared with traditional dosing, patients in the genotype-guided group reached their therapeutic international normalized ratio in a shorter time (3.8 ± 2.0 versus 4.4 ± 2.0 days, P < 0.001). There was no difference in hospitalization days (P = 0.28). CONCLUSIONS Warfarin pharmacogenetic testing according to the International Warfarin Pharmacogenetics Consortium algorithm cannot improve anticoagulation outcomes in Chinese patients with heart valve replacement.
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Kampouraki E, Kamali F. Pharmacogenetics of anticoagulants used for stroke prevention in patients with atrial fibrillation. Expert Opin Drug Metab Toxicol 2019; 15:449-458. [PMID: 31120800 DOI: 10.1080/17425255.2019.1623878] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: The inclusion of pharmacogenetics alongside clinical information in anticoagulant therapy offers the opportunity for a tailored approach to treatment according to individual patient characteristics. Areas covered: Literature was searched using PubMed database, focusing on pharmacogenetics of oral anticoagulants. Original research articles and review articles in English language were included in the literature reviewed. This article includes all information available for the genetic cause of inter-individual variability in anticoagulation response to oral anticoagulant drugs. The pharmacogenetics of VKAs and NOACs are described in detail. Expert opinion: There have been numerous studies focusing on the pharmacogenetics of VKAs, particularly warfarin. Current evidence suggests that known genetic and clinical factors explain a large proportion of the inter-individual variability in response to warfarin. Pharmacogenetic-based algorithms have been validated to determine their clinical utility with equivocal results. To date, only a limited number of mostly small studies on the pharmacogenetics of NOACs exists. The latter have highlighted genetic polymorphisms in specific genes that may affect clinical outcomes. Further evaluations of these polymorphisms are needed before firm conclusions can be drawn about the significance of pharmacogenetics on NOAC therapy.
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Affiliation(s)
- Emmanouela Kampouraki
- a Institute of Cellular Medicine within Faculty of Medical Sciences , Newcastle University , Newcastle upon Tyne , UK
| | - Farhad Kamali
- b Newcastle upon Tyne Hospitals, NHS Foundation Trust , Newcastle upon Tyne , UK
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Dorji PW, Tshering G, Na‐Bangchang K. CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South‐East and East Asian populations: A systematic review. J Clin Pharm Ther 2019; 44:508-524. [DOI: 10.1111/jcpt.12835] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 02/15/2019] [Accepted: 03/10/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Palden Wangyel Dorji
- Chulabhorn International College of Medicine, Rangsit Center Thammasat University Klong Luang Pathum Thani Thailand
| | - Gyem Tshering
- Chulabhorn International College of Medicine, Rangsit Center Thammasat University Klong Luang Pathum Thani Thailand
| | - Kesara Na‐Bangchang
- Chulabhorn International College of Medicine, Rangsit Center Thammasat University Klong Luang Pathum Thani Thailand
- Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Rangsit Center Thammasat University Klong Luang Pathum Thani Thailand
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Jorgensen AL, Prince C, Fitzgerald G, Hanson A, Downing J, Reynolds J, Zhang JE, Alfirevic A, Pirmohamed M. Implementation of genotype-guided dosing of warfarin with point-of-care genetic testing in three UK clinics: a matched cohort study. BMC Med 2019; 17:76. [PMID: 30961588 PMCID: PMC6454722 DOI: 10.1186/s12916-019-1308-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 03/15/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Warfarin is a widely used oral anticoagulant. Determining the correct dose required to maintain the international normalised ratio (INR) within a therapeutic range can be challenging. In a previous trial, we showed that a dosing algorithm incorporating point-of-care genotyping information ('POCT-GGD' approach) led to improved anticoagulation control. To determine whether this approach could translate into clinical practice, we undertook an implementation project using a matched cohort design. METHODS At three clinics (implementation group; n = 119), initial doses were calculated using the POCT-GGD approach; at another three matched clinics (control group; n = 93), patients were dosed according to the clinic's routine practice. We also utilised data on 640 patients obtained from routinely collected data at comparable clinics. Primary outcome was percentage time in target INR range. Patients and staff from the implementation group also provided questionnaire feedback on POCT-GGD. RESULTS Mean percentage time in INR target range was 55.25% in the control group and 62.74% in the implementation group; therefore, 7.49% (95% CI 3.41-11.57%) higher in the implementation group (p = 0.0004). Overall, patients and staff viewed POCT-GGD positively, suggesting minor adjustments to allow smooth implementation into practice. CONCLUSIONS In the first demonstration of the implementation of genotype-guided dosing, we show that warfarin dosing determined using an algorithm incorporating genetic and clinical factors can be implemented smoothly into clinic, to ensure target INR range is reached sooner and maintained. The findings are like our previous randomised controlled trial, providing an alternative method for improving the risk-benefit of warfarin use in daily practice.
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Affiliation(s)
- Andrea L Jorgensen
- Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, member of Liverpool Health Partners, Liverpool, UK.
| | - Clare Prince
- The Royal Liverpool and Broadgreen University Hospitals NHS Trust and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Gail Fitzgerald
- The Royal Liverpool and Broadgreen University Hospitals NHS Trust and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Anita Hanson
- The Royal Liverpool and Broadgreen University Hospitals NHS Trust and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jennifer Downing
- Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, member of Liverpool Health Partners, Liverpool, UK.,NIHR Collaboration for Leadership in Applied Health Research and Care, North West Coast, UK
| | - Julia Reynolds
- Innovation Agency, Academic Health Science Network for the North West Coast, Daresbury, Warrington, UK
| | - J Eunice Zhang
- Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, member of Liverpool Health Partners, Liverpool, UK
| | - Ana Alfirevic
- Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, member of Liverpool Health Partners, Liverpool, UK
| | - Munir Pirmohamed
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool and The Royal Liverpool and Broadgreen University Hospitals NHS Trust, members of Liverpool Health Partners, Liverpool, UK
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Richardson M, Kirkham J, Dwan K, Sloan DJ, Davies G, Jorgensen AL. NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2019; 23:293-305. [PMID: 30871660 PMCID: PMC6421944 DOI: 10.5588/ijtld.18.0324] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 08/08/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the N-acetyltransferase 2 (NAT2) gene may increase the risk of experiencing such toxicity events. OBJECTIVE To provide a comprehensive evaluation of the evidence base for associations between NAT2 variants and anti-tuberculosis drug-related toxicity. METHOD This was a systematic review and meta-analysis. We searched for studies in Medline, PubMed, EMBASE, BIOSIS and Web of Science. We included data from 41 articles (39 distinct cohorts of patients). We pooled effect estimates for each genotype on each outcome using meta-analyses stratified by country. RESULTS We assessed the quality of the included studies, which was variable, with many areas of concern. Slow/intermediate NAT2 acetylators were statistically significantly more likely to experience hepatotoxicity than rapid acetylators (OR 1.59, 95%CI 1.26-2.01). Heterogeneity was not detected in the overall pooled analysis (I² = 0%). NAT2 acetylator status was significantly associated with the likelihood of experiencing anti-tuberculosis drug-related hepatotoxicity. CONCLUSION We encountered several challenges in performing robust syntheses of data from pharmacogenetic studies, and we outline recommendations for the future reporting of pharmacogenetic studies to enable high-quality systematic reviews and meta-analyses to be performed.
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Affiliation(s)
- M Richardson
- Department of Biostatistics, University of Liverpool, Liverpool
| | - J Kirkham
- Department of Biostatistics, University of Liverpool, Liverpool
| | - K Dwan
- Cochrane Editorial Unit, London
| | - D J Sloan
- School of Medicine, University of St Andrews, St Andrews
| | - G Davies
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK
| | - A L Jorgensen
- Department of Biostatistics, University of Liverpool, Liverpool
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Shukla A, Jain A, Kahalekar V, Bendkhale S, Gogtay N, Thatte U, Bhatia S. Mutations in CYP2C9 and/or VKORC1 haplotype are associated with higher bleeding complications in patients with Budd-Chiari syndrome on warfarin. Hepatol Int 2019; 13:214-221. [PMID: 30617764 DOI: 10.1007/s12072-018-9922-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 12/18/2018] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Anticoagulation is universally recommended in Budd-Chiari syndrome [BCS]. Vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 are involved in the metabolism of warfarin. The present study was done to assess whether these mutations are associated with the risk of bleeding in patients with BCS receiving warfarin. PATIENTS AND METHODS Patients diagnosed with BCS underwent genotyping for three single nucleotide polymorphisms [SNPs]-two for the CYP2C9 and one for the VKORC1 haplotype. The patients were followed up for at least 12 months and all bleeding episodes were recorded. Patients with and without mutations were compared for bleeding complications and a crude odds ratio [crude OR] was derived for the association between bleeding and presence or absence of mutant alleles. RESULTS Eighty patients [mean (SD) age 27.47 (8.93) years, 35 male] with BCS underwent genetic testing. 37/80 (46.2%) patients had mutation of CYP2C9 and/or VKORC1; 22/80 (27.5%) had either of the mutant alleles of CYP2C9 and, similarly, 22/80 (27.5%) had the VKORC mutation. Over a median follow-up of 20 (range 12-96) months, 21/80 (26.3%) patients had bleeding complications. Patients with mutant SNPs had a higher risk of bleeding than those without [14/37 vs. 7/43, p = 0.04, crude OR (95% CI) 3.13 (1.1-8.9)]. CONCLUSION The presence of mutations in VKORC1 or CYP2C9 is associated with increased risk of bleeding in patients with BCS on warfarin. Such patients with SNPs of CY2C9 or VKORC1 haplotype should be monitored intensively while receiving warfarin.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India.
| | - Abhinav Jain
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
| | - Vinit Kahalekar
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
| | - Sheetal Bendkhale
- Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
| | - Nithya Gogtay
- Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
| | - Urmila Thatte
- Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
| | - Shobna Bhatia
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, 400012, India
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Richardson M, Kirkham J, Dwan K, Sloan DJ, Davies G, Jorgensen AL. CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis. Syst Rev 2018; 7:204. [PMID: 30458875 PMCID: PMC6247669 DOI: 10.1186/s13643-018-0861-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/29/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Treatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes. METHODS We searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies. RESULTS We included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I2 = 0%). CONCLUSIONS Generally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number: CRD42017068448.
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Affiliation(s)
- Marty Richardson
- Department of Biostatistics, University of Liverpool, Liverpool, L69 3GB UK
| | - Jamie Kirkham
- Department of Biostatistics, University of Liverpool, Liverpool, L69 3GB UK
| | - Kerry Dwan
- Cochrane Editorial Unit, London, SW1Y 4QX UK
| | - Derek J. Sloan
- School of Medicine, University of St Andrews, St Andrews, KY16 9TF UK
| | - Geraint Davies
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, L69 3GB UK
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Effect of genetic and patient factors on warfarin pharmacodynamics following warfarin withdrawal: Implications for patients undergoing surgery. Thromb Res 2018; 171:167-170. [DOI: 10.1016/j.thromres.2018.09.064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 01/18/2023]
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Tse G, Gong M, Li G, Wong SH, Wu WKK, Wong WT, Roever L, Lee APW, Lip GYH, Wong MCS, Liu T, International Health Informatics Study (IHIS) Network. Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol 2018; 84:1868-1882. [PMID: 29704269 PMCID: PMC6089819 DOI: 10.1111/bcp.13621] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/03/2018] [Accepted: 04/17/2018] [Indexed: 12/20/2022] Open
Abstract
AIMS Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. METHODS PubMed and the Cochrane Library were searched up to 23 October 2017. RESULTS A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype-guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow-up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype-guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype-guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2 : 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. CONCLUSIONS Genotype-guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident.
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Affiliation(s)
- Gary Tse
- Department of Medicine and Therapeutics, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
- Li Ka Shing Institute of Health Sciences, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
| | - Mengqi Gong
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjin300211People's Republic of China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjin300211People's Republic of China
| | - Sunny Hei Wong
- Department of Medicine and Therapeutics, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
- Li Ka Shing Institute of Health Sciences, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
| | - William K. K. Wu
- Li Ka Shing Institute of Health Sciences, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
- Department of Anaesthesia and Intensive Care, State Key Laboratory of Digestive DiseaseThe Chinese University of Hong KongHong KongSARPeople's Republic of China
| | - Wing Tak Wong
- School of Life SciencesChinese University of Hong KongHong KongSARPeople's Republic of China
| | - Leonardo Roever
- Department of Clinical ResearchFederal University of UberlândiaMGBrazil
| | - Alex Pui Wai Lee
- Department of Medicine and Therapeutics, Faculty of MedicineChinese University of Hong KongHong KongSARPeople's Republic of China
| | - Gregory Y. H. Lip
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
- Aalborg Thrombosis Research Unit, Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Martin C. S. Wong
- JC School of Public Health and Primary CareThe Chinese University of Hong KongHong KongSARPeople's Republic of China
- State Key Laboratory of Digestive DiseaseChinese University of Hong KongHong KongSARPeople's Republic of China
| | - Tong Liu
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjin300211People's Republic of China
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Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial. Ther Drug Monit 2018; 40:362-368. [DOI: 10.1097/ftd.0000000000000501] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Li J, Yang W, Xie Z, Yu K, Chen Y, Cui K. Impact of VKORC1, CYP4F2 and NQO1 gene variants on warfarin dose requirement in Han Chinese patients with catheter ablation for atrial fibrillation. BMC Cardiovasc Disord 2018; 18:96. [PMID: 29776386 PMCID: PMC5960187 DOI: 10.1186/s12872-018-0837-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 05/09/2018] [Indexed: 02/05/2023] Open
Abstract
Background The anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation. Methods A total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study. The study population included had high (≥2) risk according to the CHA2DS2-VASc risk score. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 were analyzed by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Multiple linear regression analysis was applied to depict the impact of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 on the daily stable warfarin dose requirement. Results Carriers of VKORC1 rs9923231 AG/GG genotypes required significantly higher warfarin dose (3.03 ± 0.28 mg/day, 7.19 mg/day, respectively) than AA carriers (2.52 ± 0.07 mg/day; P < 0.001). Carriers of CYP4F2 rs2108622 CT/TT genotypes required significantly higher warfarin dose (3.38 ± 0.22 mg/day, 2.79 ± 0.19 mg/day, respectively) than CC carriers (2.41 ± 0.08 mg/day; P < 0.001). However, the warfarin dose for carriers of NQO1 rs1800566 CT/TT genotypes (2.46 ± 0.24 mg/day, 3.01 ± 0.27 mg/day, respectively) was not significantly higher than that for the CC carriers (2.33 ± 0.1 mg/day). The multiple linear regression model including genotypes and demographic characteristics, could explain 20.1% of individual variations in the daily stable warfarin dose in Sichuan Han Chinese. VKORC1 rs9923231 contributed most (15%) to the individual variations in daily stable warfarin dose, while CYP4F2 rs2108622 contributed least (3%). Conclusion NQO1 rs1800566 is not a significant genetic factor of warfarin dose for Han Chinese, whereas VKORC1 rs9923231 and CYP4F2 rs2108622 are significant genetic factors, which could explain 15% and approximately 3% of individual variations in the daily stable warfarin dose respectively.
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Affiliation(s)
- Jiao Li
- College of Life Science, Sichuan Normal University, Chengdu, People's Republic of China
| | - Wenlong Yang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zhonghui Xie
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Kun Yu
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Yuhua Chen
- Department of Cardiac Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Kaijun Cui
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
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Abstract
Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual's genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein-drug or drug-drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease.
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Affiliation(s)
- Jane A Leopold
- From the Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Joseph Loscalzo
- From the Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
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44
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Bedewy AML, Sheweita SA, Mostafa MH, Kandil LS. The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians. Indian J Hematol Blood Transfus 2018; 34:328-336. [PMID: 29622878 DOI: 10.1007/s12288-016-0725-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 09/19/2016] [Indexed: 10/20/2022] Open
Abstract
Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase. This protein is encoded by vitamin K epoxide reductase complex subunit 1 gene (VKORC1). The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin. One hundred cases starting warfarin treatment and 20 healthy controls were enrolled. The mean daily dose of warfarin was calculated from patient's medical records. For each patient, less than 10 % variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range were required for at least 3 months for one of the following indications (deep vein thrombosis, pulmonary embolism, cerebrovascular stroke and myocardial infarction) prior to inclusion in the study. Tetraprimer amplification refractory mutation system PCR was performed to determine CYP2C9*2, CYP2C9*3, and the VKORC1 1639 G > A genetic polymorphisms. Plasma warfarin determination was performed using rapid fluorometric assay. Plasma warfarin concentration ranged from 2.19 to 10.98 μg/ml with a median 3.52 μg/ml. Supratherpeutic INR was observed in 11 % of the cases. Thromboembolic complications occurred in 7 % of the cases and 8 % of cases experienced major bleeding. High maintenance dose (>7 mg/day) was associated with the combined non VKORC1*2 and homozygous wild type CYP2C9 (CYP2C9*1*1) alleles, while low maintenance dose was associated with the Variant (AG + AA)/Wild (*1/*1). (p value <0.001). CYP2C9 variant was a risk factor for supratherapeutic INR in the multivariate logistic regression model. Thromboembolic complication and incidence of supratherapeutic INR were observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3). Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients.
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Affiliation(s)
- Ahmed M L Bedewy
- 1Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.,Abraj Al-Shaker, Zaky Ragab Street, Smouha, Alexandria, 21615 Egypt
| | - Salah A Sheweita
- 2Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | - Mostafa Hasan Mostafa
- 2Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | - Lamia Saeed Kandil
- 3Biochemistry Department, Pharos University in Alexandria, Alexandria, Egypt
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45
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Osanlou O, Pirmohamed M, Daly AK. Pharmacogenetics of Adverse Drug Reactions. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 83:155-190. [PMID: 29801574 DOI: 10.1016/bs.apha.2018.03.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Genetic factors predispose to many ADRs, affecting susceptibility to both type A and type B reactions. The overall contribution of genetics will vary according to drug and ADR, and should be considered when attempting to predict and prevent ADRs. Genetic risk factors are considered in detail for a number of type A ADRs, especially those relating to warfarin and thiopurines, and type B ADRs affecting skin, the liver, and the heart. As the availability of whole genome sequencing increases, it is likely that prospective genotype for particular ADRs prior to drug prescription will become more common in the future. Current examples of genetic testing to prevent ADRs which have already been implemented and future prospects for developments in the field are discussed in detail.
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Affiliation(s)
- Orod Osanlou
- Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom
| | - Ann K Daly
- Institute of Cellular Medicine, Newcastle University, Medical School, Newcastle upon Tyne, United Kingdom.
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46
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Floyd JS, Sitlani CM, Avery CL, Noordam R, Li X, Smith AV, Gogarten SM, Li J, Broer L, Evans DS, Trompet S, Brody JA, Stewart JD, Eicher JD, Seyerle AA, Roach J, Lange LA, Lin HJ, Kors JA, Harris TB, Li-Gao R, Sattar N, Cummings SR, Wiggins KL, Napier MD, Stürmer T, Bis JC, Kerr KF, Uitterlinden AG, Taylor KD, Stott DJ, de Mutsert R, Launer LJ, Busch EL, Méndez-Giráldez R, Sotoodehnia N, Soliman EZ, Li Y, Duan Q, Rosendaal FR, Slagboom PE, Wilhelmsen KC, Reiner AP, Chen YDI, Heckbert SR, Kaplan RC, Rice KM, Jukema JW, Johnson AD, Liu Y, Mook-Kanamori DO, Gudnason V, Wilson JG, Rotter JI, Laurie CC, Psaty BM, Whitsel EA, Cupples LA, Stricker BH. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. THE PHARMACOGENOMICS JOURNAL 2018; 18:127-135. [PMID: 27958378 PMCID: PMC5468495 DOI: 10.1038/tpj.2016.90] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 10/25/2016] [Accepted: 11/14/2016] [Indexed: 12/17/2022]
Abstract
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.
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Affiliation(s)
- James S Floyd
- Deparments of Epidemiology and Medicine, University of Washington, Seattle, WA, USA
| | | | - Christy L Avery
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Raymond Noordam
- Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Xiaohui Li
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Albert V Smith
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykavik, Iceland
| | | | - Jin Li
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Linda Broer
- Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Daniel S Evans
- California Pacific Medical Center Research Institute, San Francisco, CA, USA
| | - Stella Trompet
- Department of Cardiology and Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Jennifer A Brody
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - James D Stewart
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
- Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA
| | - John D Eicher
- Population Sciences Branch, National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA USA
- The Framingham Heart Study, Framingham, MA, USA
| | - Amanda A Seyerle
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - Jeffrey Roach
- Research Computing Center, University of North Carolina, Chapel Hill, NC
| | - Leslie A Lange
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Henry J Lin
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
- Division of Medical Genetics, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Jan A Kors
- Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Tamara B Harris
- Laboratory of Epidemiology, Demography, and Biometry, National Institue on Aging, Bethesda, MD, USA
| | - Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom
| | - Steven R Cummings
- California Pacific Medical Center Research Institute, San Francisco, CA, USA
| | - Kerri L Wiggins
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Melanie D Napier
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Til Stürmer
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
- Center for Pharmacoepidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Joshua C Bis
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Kathleen F Kerr
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - André G Uitterlinden
- Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
| | - David J Stott
- Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Scotland, United Kingdom
| | - Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lenore J Launer
- Laboratory of Epidemiology, Demography, and Biometry, National Institue on Aging, Bethesda, MD, USA
| | - Evan L Busch
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Nona Sotoodehnia
- Deparments of Epidemiology and Medicine, University of Washington, Seattle, WA, USA
| | - Elsayed Z Soliman
- Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Yun Li
- Department of Biostatistics, Computer Science, and Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Qing Duan
- Research Computing Center, University of North Carolina, Chapel Hill, NC
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - P Eline Slagboom
- Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Kirk C Wilhelmsen
- Research Computing Center, University of North Carolina, Chapel Hill, NC
- The Renaissance Computing Institute, Chapel Hill, NC, USA
| | - Alexander P Reiner
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Yii-Der I Chen
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Susan R Heckbert
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kenneth M Rice
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
- Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
| | - Andrew D Johnson
- Population Sciences Branch, National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA USA
- The Framingham Heart Study, Framingham, MA, USA
| | - Yongmei Liu
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA
| | - Dennis O Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykavik, Iceland
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Cathy C Laurie
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Bruce M Psaty
- Departments of Epidemiology, Health Services, and Medicine, University of Washington, Seattle, WA, USA
- Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA
| | - Eric A Whitsel
- Departments of Epidemiology and Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - L Adrienne Cupples
- The Framingham Heart Study, Framingham, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Bruno H Stricker
- Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
- Inspectorate of Health Care, Utrecht, the Netherlands
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47
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Hosseinkhani Z, Sadeghalvad M, Norooznezhad F, Khodarahmi R, Fazilati M, Mahnam A, Fattahi A, Mansouri K. The effect of CYP2C9*2, CYP2C9*3, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah. Res Pharm Sci 2018; 13:377-384. [PMID: 30065771 PMCID: PMC6040167 DOI: 10.4103/1735-5362.235165] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
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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Affiliation(s)
- Zohreh Hosseinkhani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran.,Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Mona Sadeghalvad
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran.,Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Fathemeh Norooznezhad
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Mohammad Fazilati
- Department of Biochemistry, Payam-e Noor University of Isfahan, Isfahan, I.R. Iran
| | - Azadeh Mahnam
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Ali Fattahi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
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48
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Tornio A, Backman JT. Cytochrome P450 in Pharmacogenetics: An Update. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 83:3-32. [PMID: 29801580 DOI: 10.1016/bs.apha.2018.04.007] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Interindividual variability in drug disposition is a major cause of lack of efficacy and adverse effects of drug therapies. The majority of hepatically cleared drugs are metabolized by cytochrome P450 (CYP) enzymes, mainly in families CYP1, CYP2, and CYP3. Genes encoding these enzymes are highly variable with allele distribution showing considerable differences between populations. Genetic variability of especially CYP2C9, CYP2C19, CYP2D6, and CYP3A5 is known to have clear clinical impact on drugs that are metabolized by these enzymes. CYP1A2, CYP2A6, CYP2B6, CYP2C8, and CYP3A4 all show variability that affects pharmacokinetics of drugs as well, but so far the evidence regarding their clinical implications is not as conclusive. In this review, we provide an up-to-date summary of the pharmacogenetics of the major human drug-metabolizing CYP enzymes, focusing on clinically significant examples.
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Affiliation(s)
- Aleksi Tornio
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Janne T Backman
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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49
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Daly AK, Rettie AE, Fowler DM, Miners JO. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J Pers Med 2017; 8:E1. [PMID: 29283396 PMCID: PMC5872075 DOI: 10.3390/jpm8010001] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 02/07/2023] Open
Abstract
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.
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Affiliation(s)
- Ann K Daly
- Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
| | - Allan E Rettie
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
| | - Douglas M Fowler
- Department of Genome Sciences and Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
| | - John O Miners
- Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide 5042, Australia.
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50
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Cai LL, Huang WQ, Su ZY, Ye HM, Wang LS, Wu Y, Zhang ZY, Zhang W, Tzeng CM. Identification of two novel genes SLC15A2 and SLCO1B3 associated with maintenance dose variability of warfarin in a Chinese population. Sci Rep 2017; 7:17379. [PMID: 29234073 PMCID: PMC5727167 DOI: 10.1038/s41598-017-17731-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 11/29/2017] [Indexed: 01/12/2023] Open
Abstract
Warfarin is a commonly prescribed and effective oral anticoagulant. Genetic polymorphisms associated with warfarin metabolism and sensitivity have been implicated in the wide inter-individual dose variation that is observed. Several algorithms integrating patients’ clinical characteristics and genetic polymorphism information have been explored to predict warfarin dose. However, most of these algorithms could explain only over half of the variation in a warfarin maintenance dose, suggesting that additional genetic factors may exist and need to be identified. Here, a drug absorption, distribution, metabolism and excretion (ADME) Core Panel Kit-based pharmacogenetic study was performed to screen for warfarin dose-associated SNP sites in Han-Chinese population patients taking warfarin therapy, and the screen was followed by pyrosequencing-based validation. Finally, we confirmed that the common variant rs9923231 in VKORC1 and two novel genes, SLC15A2 (rs1143671 and rs1143672) and SLCO1B3 (rs4149117 and rs7311358), are associated with the warfarin maintenance dose. As has been shown for those carriers with the variant rs9923231 in VKORC1, it was suggested that those subjects with homozygous minor alleles in those four SNPs should take a lower warfarin dose than those carrying the wild type alleles. Together with the established predictor rs9923231 in VKORC1, those four novel variants on SLC15A2 and SLCO1B3 should be considered as useful biomarkers for warfarin dose adjustment in clinical practice in Han-Chinese populations.
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Affiliation(s)
- Liang-Liang Cai
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Sheng, China
| | - Wen-Qing Huang
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Sheng, China
| | - Zhi-Ying Su
- Clinical Research Laboratory, Xiamen's Maternal and Child Health Hospital, Teaching Hospital of Xiamen University, Xiamen, Fujian Sheng, China
| | - Hui-Ming Ye
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Sheng, China.,Clinical Research Laboratory, Xiamen's Maternal and Child Health Hospital, Teaching Hospital of Xiamen University, Xiamen, Fujian Sheng, China
| | - Lian-Sheng Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan Sheng, China
| | - Yuan Wu
- Department of cardiac surgery, Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, Fujian Sheng, China
| | - Zhong-Ying Zhang
- Department of Clinical laboratory, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Sheng, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan Sheng, China.
| | - Chi-Meng Tzeng
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Sheng, China.
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