Effect of <scp>CYP</scp>4F2,<scp>VKORC</scp>1, and <scp>CYP</scp>2C9 in Influencing Coumarin Dose: A Single‐Patient Data Meta‐Analysis in More Than 15,000 Individuals

Danese, Elisa; Raimondi, Sara; Montagnana, Martina; Tagetti, Angela; Langaee, Taimour; Borgiani, Paola; Ciccacci, Cinzia; Carcas, Antonio J.; Borobia, Alberto M.; Tong, Hoi Y.; Dávila-Fajardo, Cristina Lucía; Botton, Mariana Rodrigues; Bourgeois, Stéphane; Deloukas, Panos; Caldwell, Michael D.; Burmester, Jim K; Berg, Richard L.; Cavallari, Larisa H.; Drozda, Katarzyna; Huang, Min; Zhao, Lizi; Cen, Hanjing; Gónzález-Conejero, Rocío; Roldán, Vanessa; Nakamura, Yusuke; Mushiroda, Taisei; Gong, Inna Y.; Kim, Richard B.; Hirai, Keita; Itoh, Ken; Isaza, Carlos; Beltrán, Leonardo; Jiménez-Varo, Enrique; Cañadas-Garre, Marisa; Giontella, Alice; Kringen, Marianne Kristiansen; Haug, Kari Bente Foss; Gwak, Hye Sun; Lee, Jun Young; Minuz, Pietro; Lee, Ming Ta Michael; Lubitz, Steven A.; Scott, Stuart A.; Mazzaccara, Cristina; Sacchetti, Lucia; Genç, Ece; Özer, Mahmut; Pathare, Anil; Krishnamoorthy, Rajagopal; Páldi, Andràs; Siguret, Virginie; Loriot, Marie‐Anne; Kutala, Vijay Kumar; Suarez‐Kurtz, Guilherme; Perini, Jamila Alessandra; Denny, Josh C.; Ramirez, Andrea H.; Mittal, Balraj; Rathore, Saurabh Singh; Sagreiya, Hersh; Altman, Russ B.; Shahin, Mohamed H.; Khalifa, Sherief; Limdi, Nita A.; Rivers, Charles A.; Shendre, Aditi; Dillon, Chrisly; Suriapranata, Ivet; Zhou, Hong‐Hao; Tan, Sheng-Lan; Tatarūnas, Vacis; Lesauskaitė, Vaiva; Zhang, Yumao; Zee, Anke‐Hilse Maitland‐van der; Verhoef, Talitha I.; Boer, Anthonius de; Taljaard, Monica; Zambon, Carlo–Federico; Pengo, Vittorio; Zhang, Jieying Eunice; Pirmohamed, Munir; Johnson, Julie A.; Fava, Cristiano

doi:10.1002/cpt.1323

Cited by 27 publications

(15 citation statements)

References 58 publications

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“…The contribution of clinical molecular biology in the evaluation and prevention of cardiological risk, in particular sudden cardiac death, and in the therapeutic approach [ 178 ], both in patients and in healthy subjects and athletes, is an important goal that involves many areas of the medical profession [ 179 , 180 , 181 , 182 , 183 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Mazzaccara

Mirra

Barretta

et al. 2021

IJMS

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Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.

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Section: Discussionmentioning

confidence: 99%

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Mazzaccara

Mirra

Barretta

et al. 2021

IJMS

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“…Despite the contribution of pharmacogenetic algorithms to explain the variability in the dosing of coumarin drugs, doubts remain about their applicability in routine clinical practice. Several clinical trials and metanalyses have been published to date on warfarin but with inconclusive results [25][26][27][28][29][30]. In the case of acenocoumarol, the results of the only two available clinical trials on acenocoumarol are also inconclusive.…”

Section: Discussionmentioning

confidence: 99%

“…A number of meta-analyses have been published showing that genotype-guided dosing improves the percentage of time within the therapeutic INR range [24][25][26], although the usefulness of the pharmacogenetics in reducing bleeding complications is a subject of debate [24,[26][27][28]. To date, there have been only two published clinical trials on acenocoumarol evaluating two different pharmacogenetic algorithms, with conflicting results [22,23], and a few meta-analyses within the context of studies assessing the effect of including genetic variables in the dosing of coumarins [25,[28][29][30]. Most of these studies (with both warfarin and acenocoumarol) included a mixed population.…”

Section: Introductionmentioning

confidence: 99%

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial

Tong¹,

Borobia

Quintana-Díaz

et al. 2021

JCM

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Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.

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“…Recently, a meta-analysis has been published [104] including 15,754 patients. The CYP4F2 *3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% CI 7–10%), with a larger effect in females, in patients taking acenocoumarol, and in Europeans.…”

Section: The Most Relevant Evidence In Pharmacogenetics Of Drugs Umentioning

confidence: 99%

“…The inclusion of the CYP4F2 *3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived [104].…”

Section: The Most Relevant Evidence In Pharmacogenetics Of Drugs Umentioning

confidence: 99%

Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine

Dávila-Fajardo

Díaz-Villamarín

Antúnez-Rodríguez

et al. 2019

Genes

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There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice.

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Effect of CYP4F2,VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single‐Patient Data Meta‐Analysis in More Than 15,000 Individuals

Cited by 27 publications

References 58 publications

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial

Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine

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