Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.
Elisa DaneseSara RaimondiMartina MontagnanaAngela TagettiTaimour LangaeePaola BorgianiCinzia CiccacciAntonio J CarcasAlberto M BorobiaHoi Y TongCristina Dávila-FajardoMariana Rodrigues BottonStephane BourgeoisPanagiotis DeloukasMichael D CaldwellJim K BurmesterRichard L BergLarisa H CavallariKatarzyna DrozdaMin HuangLi-Zi ZhaoHan-Jing CenRocio Gonzalez-ConejeroVanessa Roldán SchillingYusuke NakamuraTaisei MushirodaInna Y GongRichard B KimKeita HiraiKunihiko ItohCarlos IsazaLeonardo BeltránEnrique Jiménez-VaroMarisa Cañadas-GarreAlice GiontellaMarianne K KringenKari Bente Foss HaugHye Sun GwakKyung Eun LeePietro MinuzMing Ta Michael LeeSteven A LubitzStuart A ScottCristina MazzaccaraLucia SacchettiEce GençMahmut ÖzerAnil PathareRajagopal KrishnamoorthyAndras PaldiVirginie SiguretMarie-Anne LoriotVijay Kumar KutalaGuilherme Suarez-KurtzJamila PeriniJoshua C DennyAndrea H RamirezBalraj MittalSaurabh Singh RathoreHersh SagreiyaRuss B AltmanMohamed Hossam A ShahinSherief I KhalifaNita A LimdiCharles RiversAditi ShendreChrisly DillonIvet M SuriapranataHong-Hao ZhouSheng-Lan TanVacis TatarunasVaiva LesauskaiteYumao ZhangAnke H Maitland-van der ZeeTalitha I VerhoefAnthonius de BoerMonica TaljaardCarlo Federico ZambonVittorio PengoJieying Eunice ZhangMunir PirmohamedJulie A JohnsonCristiano FavaPublished in: Clinical pharmacology and therapeutics (2019)
The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. 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.
Keyphrases
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- systematic review
- peritoneal dialysis
- prognostic factors
- randomized controlled trial
- type diabetes
- pregnant women
- patient reported outcomes
- metabolic syndrome
- insulin resistance
- big data
- fluorescent probe
- copy number
- drug induced
- data analysis