Verification of pharmacogenomics-based algorithms to predict warfarin maintenance dose using registered data of Japanese patients
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Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9 (CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences.
Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097–1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC).
For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy.
The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.
KeywordsWarfarin Algorithm VKORC1 CYP2C9 CYP4F2
We are grateful to all doctors, nurses, and subjects who participated in this study.
Conceived and designed the experiments: MO, HN, YF, MM. Performed the experiments: MS, YF, SN, MM. Analyzed the data: MO, SN, SH, SM, YF, YM, JY, YS, YF, MM. Contributed new methods or models: YF, MM. Wrote the paper: YF, MM.
This study was funded by the Management Expenses Grants from MEXT, Japan.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Ethical Review Committee of Osaka University (approval number, 766). Written informed consent was obtained from each participant to allow their samples and clinical data to be used for secondary analyses. For this type of study formal consent is not required. The study has been performed in accordance with The Code of Ethics of the 1964 Declaration of Helsinki and its later amendments. This study does not contain any studies with animals performed by any of the authors.
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