A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9.
BACKGROUND
Because of the unique lack of genetic diversity despite the multiethnicity in the Asian population, we hypothesize that single-nucleotide polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9*3) and vitamin K epoxide reductase complex subunit 1 (VKORC1) at position 381, used to infer VKORC1haplotype in combination with demographic factors, can accurately predict warfarin doses. The aims of this study were to derive a pharmacogenetics-based dosing algorithm by use of retrospective information and to validate it through a data-splitting method in a separate cohort of equal size.


METHODS
We used 215 records of warfarin patients recruited into a CYP2C9/VKORC1 genotyping study to perform this analysis. Univariate analyses for individual predictors, including age, weight, gender, serum albumin concentration, ethnic group, international normalized ratio, and CYP2C9 and VKORC1 381 genotypes, were conducted to select variables with P < .1 for further inclusion into the multivariate regression analysis. In the final model only predictors reaching a statistical significance of P < .05 were retained.


RESULTS
Data from 107 subjects undergoing maintenance warfarin therapy with an international normalized ratio stabilized between 2 and 3 were used to derive the final model, as an exponential function of age, weight, CYP2C9*3 allele, and VKORC1 381 CC and TC genotypes, and this model accounted for 60.2% of the variability in daily warfarin dose requirement. The model was validated in a separate cohort of 108 subjects and showed a mean underestimation of 0.23 +/- 1.21 mg/d.


CONCLUSIONS
Warfarin dose requirements in Asians can be accurately predicted by use of a combination of patient demographics and a simplified genotyping approach for single variants in CYP2C9 and VKORC1.
Tham
Lai-San
LS
Department of Haematology-Oncology, National University Hospital, and Translational Interface, Oncology Research Institute, Singapore.
Goh
Boon-Cher
BC
Nafziger
Anne
A
Guo
Jia-Yi
JY
Wang
Ling-Zhi
LZ
Soong
Richie
R
Lee
Soo-Chin
SC
D000328:Adult; D000368:Aged; D000465:Algorithms; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001213:Asian / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases