[Establishment and evaluation of a warfarin-dosing algorithm in Chinese Han population].

OBJECTIVE: To develop and evaluate a warfarin-dosing algorithm method which can be used to guide the adjustment of warfarin maintenance dose in Chinese Han population. METHODS: A total of 512 patients with steady warfarin taking were recruited from Beijing Hospital during May 2012 to December 2014. Indications for warfarin prescribing included prosthetic heart valve, atrial fibrillation and pulmonary embolism. Genomic DNAs were extracted from blood samples and used for the genetic polymorphism analysis of VKORC1 and CYP2C9 (include (*)3 and (*)13 alleles). Warfarin dose, demographic variabilities and amiodarone compliance were recorded during regular visit. These patients were randomly divided into groups using the method of random number table, 384 patients were randomly selected as derivation group, the remaining 128 cases as the validation group.Using data from derivation group, a warfarin-dosing algorithm was established based on the genetic information, demographic characteristics and concomitant compliance by a multiple linear regression analysis parameter. Then the accuracy of newly developed algorithm method was further evaluated by comparing the predicting dose with the actual dose in the validation group. RESULTS: The stable dose of warfarin was tightly associated with factors like age, height, weight, VKORC1 -1639G>A, CYP2C9(*)3, CYP2C9(*)13 and amiodarone usage. Newly developed algorithm method exhibited better prediction effect (R(2)=0.682, P<0.01) as compared with that of previously reported algorithm methods. The weights of VKORC1 and CYP2C9 for predicting of warfarin dosage were estimated to more than 50%. Using this method, 62.5% of patients in the validation group could be well recognized, in which the predicting dose of warfarin was within 20% of the actual dose, and only 7.81% patients showed underestimated prediction warfarin dose while 29.69% patients showed overestimated values. CONCLUSION: Newly developed algorithm method can be used for the guidance of warfarin maintenance dose adjustment in Chinese Han population.

Characterization of a novel CYP2C9 mutation (1009C>A) detected in a warfarin-sensitive patient.

Warfarin is the most frequently prescribed anticoagulant for the long-term treatment in the clinic. Recent studies have shown that polymorphic alleles within the CYP2C9, VKORC1, and CYP4F2 genes are related to the warfarin dosage requirement. In this study, a novel non-synonymous mutation (1009C>A) in CYP2C9 was detected in a warfarin-hypersensitive patient, while the other two candidate genes were both found to be homozygous for the wild-type alleles. The newly identified point mutation results in an amino acid substitution at position 337 of the CYP2C9 protein (P337T) and has been designated as the novel allele CYP2C9*58. When expressed in insect cell microsomes, the relative intrinsic clearance values of the CYP2C9.58 variant for tolbutamide and losartan were quite similar to those of the typical defective variant CYP2C9.3, whereas the clearance value of CYP2C9.58 for diclofenac was slightly higher than that of another typical defective variant CYP2C9.2. These data suggested that when compared with wild-type CYP2C9.1, the enzymatic activity of the novel allelic variant has been greatly reduced by the 1009C>A mutation. If patients carrying this allele take drugs metabolized by CYP2C9, their metabolic rate might be slower than that of wild-type allele carriers and thus much more attention should be paid to their clinical care.