Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Danese E

PROVIDER: S-EPMC6542461 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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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.

Danese Elisa E Raimondi Sara S Montagnana Martina M Tagetti Angela A Langaee Taimour T Borgiani Paola P Ciccacci Cinzia C Carcas Antonio J AJ Borobia Alberto M AM Tong Hoi Y HY Dávila-Fajardo Cristina C Rodrigues Botton Mariana M Bourgeois Stephane S Deloukas Panos P Caldwell Michael D MD Burmester Jim K JK Berg Richard L RL Cavallari Larisa H LH Drozda Katarzyna K Huang Min M Zhao Li-Zi LZ Cen Han-Jing HJ Gonzalez-Conejero Rocio R Roldan Vanessa V Nakamura Yusuke Y Mushiroda Taisei T Gong Inna Y IY Kim Richard B RB Hirai Keita K Itoh Kunihiko K Isaza Carlos C Beltrán Leonardo L Jiménez-Varo Enrique E Cañadas-Garre Marisa M Giontella Alice A Kringen Marianne K MK Haug Kari Bente Foss KBF Gwak Hye Sun HS Lee Kyung Eun KE Minuz Pietro P Lee Ming Ta Michael MTM Lubitz Steven A SA Scott Stuart S Mazzaccara Cristina C Sacchetti Lucia L Genç Ece E Özer Mahmut M Pathare Anil A Krishnamoorthy Rajagopal R Paldi Andras A Siguret Virginie V Loriot Marie-Anne MA Kutala Vijay Kumar VK Suarez-Kurtz Guilherme G Perini Jamila J Denny Josh C JC Ramirez Andrea H AH Mittal Balraj B Rathore Saurabh Singh SS Sagreiya Hersh H Altman Russ R Shahin Mohamed Hossam A MHA Khalifa Sherief I SI Limdi Nita A NA Rivers Charles C Shendre Aditi A Dillon Chrisly C Suriapranata Ivet M IM Zhou Hong-Hao HH Tan Sheng-Lan SL Tatarunas Vacis V Lesauskaite Vaiva V Zhang Yumao Y Maitland-van der Zee Anke H AH Verhoef Talitha I TI de Boer Anthonius A Taljaard Monica M Zambon Carlo Federico CF Pengo Vittorio V Zhang Jieying Eunice JE Pirmohamed Munir M Johnson Julie A JA Fava Cristiano C Fava Cristiano C

Clinical pharmacology and therapeutics 20190217 6

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 systema ...[more]

PMID: 30506689

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Project description:We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

Dataset Information

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

Publications

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

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