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Blood, Vol. 113, Issue 4, 784-792, January 22, 2009
The largest prospective warfarin-treated cohort supports genetic forecasting
Blood Wadelius et al.
113: 784
Supplemental materials for: Wadelius et al
Files in this Data Supplement:
- Table S1. Drugs assessed as interacting with warfarin (PDF, 74.3 KB) -
They are sorted according to the Anatomical Therapeutic Chemical Classification System (ATC code) which is developed by the World Health Organization’s Collaborating Centre for Drug Statistics Methodology.
- Table S2. Univariate ANOVA results for square root of dose in therapeutic range for all successfully genotyped SNPs in the WARG cohort (n=183) and corresponding results in the pilot study.10 (PDF, 152 KB) -
MAF is the minor allele frequency of the SNP in the WARG cohort. R2 shows the percent of the dose that can be explained by the SNP. Meff indicates that the p-value is significant at an experiment-wide level, *** p ≤ 0.001, ** p ≤ 0.01 and * p ≤ 0.05.
- Figure S1. The 29 candidate genes in the warfarin interactive pathways (JPG, 58.6 KB)
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Biotransformation of vitamin K:
• Vitamin K cycle: Vitamin K epoxide reductase - VKORC1, Microsomal Epoxide hydrolase 1 - EPHX1, NAD(P)H dehydrogenase, quinone 1 - NQO1, Calumenin - CALU, Gamma-glutamyl carboxylase - GGCX
• Vitamin K-dependent proteins: Coagulation factor II (prothrombin) - F2, Coagulation factor VII - F7, Coagulation factor IX - F9, Coagulation factor X - F10, Protein C – PROC, Protein S - PROS1, Protein Z – PROZ, Growth-arrest specific 6 - GAS6
• Other clotting proteins: Anti-thrombin III - SERPINC1, Coagulation factor V - F5
• Transportation: Apolipoprotein E - APOE
Biotransformation of warfarin:
• Metabolism: Cytochrome P450 2C9 - CYP2C9, Cytochrome P450 2C8 - CYP2C8, Cytochrome P450 2C18 - CYP2C18, Cytochrome P450 2C19 - CYP2C19, Cytochrome P450 1A1 - CYP1A1, Cytochrome P450 1A2 - CYP1A2, Cytochrome P450 3A4 - CYP3A4, Cytochrome P450 3A5 - CYP3A5
• Cytochrome P450 inducibility: Pregnane X receptor (PXR) - NR1I2, Constitutive androstane receptor (CAR) - NR1I3
• Transportation: P-glycoprotein (Multidrug resistance protein 1) - ABCB1, Alpha-1-acid glycoprotein 1 (Orosomucoid 1) - ORM1, Alpha-1-acid glycoprotein 2 (Orosomucoid 2) – ORM2.
- Figure S2. Box plots of mean weekly warfarin doses related to genotypes of VKORC1 and CYP2C9 (JPG, 65.7 KB)
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The horizontal line indicates the median, the box covers the 25¬ and 75% percentiles, and the maximum length of each whisker is 1.5 times the interquartile range. Points outside this show up as outliers. (A) VKORC1 rs9923231 (−1639 G>A) explains 29.3% of the variance in maintenance dose (p= 1.03 × 10−97). rs9923231 is utilised in this graph since it is possibly functional. (B) CYP2C9 *2 and *3 explain 11.8% of the variance in maintenance dose (p=6.63 × 10−34).
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