Genetic variants predicting warfarin sensitivity

A warfarin-sensitive technology, applied in the field of warfarin, can solve the problems of unexplainable diversity, unexplainable warfarin dose diversity, etc.

Active Publication Date: 2008-03-12
ACAD SINIC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0044] However, these studies cannot account for the variability in all warfarin doses, especially among ethnic groups, nor in the Asian population, which makes up a large portion of the world's population.

Method used

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  • Genetic variants predicting warfarin sensitivity
  • Genetic variants predicting warfarin sensitivity
  • Genetic variants predicting warfarin sensitivity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Example 1. Among the selected Chinese patients with warfarin sensitivity or resistance CYP2C9 and VKORC1 DNA sequence variants

[0127] The average maintenance dose of warfarin for Chinese is 3.3mg / day [8,9]. We therefore considered warfarin-sensitive patients receiving maintenance doses ≤1.5 mg / day (see 1, 11 patients) and warfarin-resistant patients receiving maintenance doses ≥6 mg / day (see Table 1, 5 patients, see Materials and Methods, supra). Sequencing of the coding region, exon-intron junctions, and promoter regions of the CYP2C9 gene revealed three sequence variants in 4 of 11 warfarin-sensitive patients. The variations are: 1075A>C (I359L is CYP2C9*3), 895A>G (T299A) and 1145C>T (P382L). CYP2C9*3 was detected in 3 patients (see Table 1, subjects 1, 3, 5). In addition to CYP2C9*3, subject 5 also had 895A>G (T299A) changes, as mentioned above [7]. A novel exonic mutation 1145C>T (P382L) was detected in a fourth patient (individual 6). As shown in Table ...

Embodiment 2

[0133] Example 2. VKORC1-1639G>A among random Chinese patients receiving warfarin polymorphism

[0134] To further investigate whether the -1639G>A polymorphism was associated with interindividual differences in warfarin dose, we genotyped 104 patients receiving warfarin regardless of dose using MALDI-TOF mass spectrometry. The AA and AG / GG groups did not differ in terms of age, sex and INR (see Table 2). Only two patients were found to be homozygous for GG and were included in the AG population for statistical analysis. We analyzed the data without considering the presence of other confounding variables, such as diet or other medications. As shown in Table 2, the AA group had significantly lower dose requirements (2.61 mg / day) compared to the AG / GG group (3.81 mg / day). This difference was significant between the AA and AG / GG populations whether using the T-test (p<0.0001) or the Wilcoxon-Mann-Whitney test (p=0.0002).

[0135] Table 2. Mean doses of patients randomly se...

Embodiment 3

[0138] Example 3, VKORC1-1639 G>A polymorphism of Chinese and Caucasians and Genotype frequency of CYP2C9 variants

[0139] The Chinese population is known to have much lower maintenance doses of warfarin than Caucasians. To test whether frequency differences in VKORC1-1639 genotypes could explain interethnic differences in warfarin dosing, 95 normal Han Chinese subjects and 92 normal Caucasian subjects were genotyped. In the Caucasian population, AA homozygosity had the lowest frequency, while AG and GG genotypes accounted for the majority of the population (14.2%, 46.7%, and 39.1%, respectively) (see Table 3). On the contrary, in the Chinese population, homozygous AA accounted for the majority (82.1%) of the population, and the rest were AG heterozygous (17.9%). No GG homozygotes were found in randomly selected populations. This proportion was similar to that of 104 warfarin-treated patients, of which 79.8% were homozygous for AA, 18.3% were heterozygous for AG, and on...

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Abstract

We discovered that a polymorphism in the promoter of the VKORCI gene is associated with warfarin sensitivity. This polymorphism can explain both the interindividual and inter-ethnic differences in warfarin dose requirements. Furthermore, the polymorphism is also associated with promoter activity. Thus, the promoter sequence or activity of the VKORCI gene of a subject can be used to predict how much warfarin should be prescribed for the subject. Relevant methods and compositions are provided.

Description

[0001] 【Cross Application】 [0002] This application claims the benefit of US Provisional Application 60 / 638,837, filed November 21, 2004, and US Provisional Application 60 / 679,694, filed May 10, 2005. The contents of these applications are incorporated herein by reference in their entirety. 【Technical field】 [0003] The present invention relates to a method for determining the dose of a drug, in particular warfarin. [0004] comparison file [0005] 1. Hirsh, J. (1992) Antithrombotic therapy in deep vein thrombosis and pulmonary embolism. Am. Heart J., 123, 1115-1122. [0006] 2. Laupacis, A., Albers, G., Dalen, J., Dunn, M., Feinberg, W. and Jacobson, A. (1995) Antithrombotic therapy in atrial fibrillation. Chest, 108, 352S-359S. [0007] 3. Stein, P.D., Alpert, J.S., Copeland, J., Dalen, J.E., Goldman, S. and Turpie, A.G. (1995) Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest, 108, 371S-379S. [0008] 4. Hirsh, J., Dalen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q2600/106C12Q1/6883C12Q2600/172C12Q2600/156C12Q2600/16A61P7/02C12Q1/6827
Inventor 陈垣崇阮相宇陈锦泽
Owner ACAD SINIC
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