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Genetic Testing Lab

Test Catalog Molecular Genetics Laboratory P450 CYP2C9 VKORC1 Polymorphism Analysis

P450 CYP2C9 VKORC1 Polymorphism Analysis

Test Description:

The human cytochrome CYP2C9 gene spans a region of approximately 55 kilobases and is composed of nine exons (De Morais et al., 1993). The gene resides on chromosome 10 (q24) and is clustered among other closely related 2C-genes in the order: Cen-2C18-2C19-2C9-2C8-Tel.

The CYP2C family is responsible for metabolizing a variety of exogenous and endogenous substrates and approximately 20% of currently prescribed drugs. In particular, 2C9 has a central role in the phase 1 metabolism of several medications with a narrow therapeutic index (NTI), the best characterized of which include warfarin and phenytoin. The 2C9 variant nomenclature adopted follows that outlined by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/). Variants are accordingly classified as *2 to *12.

The human VKORC1 gene, encoding Vitamin K Epoxide Reductase (VKOR), spans a region of approximately 11 kilobases on chromosome 16 (p11.2) and is composed of 3 exons. VKOR is involved in the recycling of vitamin K from its oxidized to reduced form and is the substrate for warfarin in vivo.

The test screens for the five most common variants of P450-2C9 seen across various ethnic groups (2C9*2–2C9*6), six VKORC1 coding mutations which confer a high-resistance phenotype, and the maintenance-dose defining warfarin resistance polymorphism (-1639 G to A).

References:
1. De Morais SM et al. (1993) Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18. Biochem Biophys Res Commun. 194:194-201.
2. Gray IC et al. (1995) A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics. 28:328-332.
3. Rettie AE et al. (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P450: a role for P450-2C9 in the etiology of (S)-warfarin drug interactions. Chem Res. Toxicol. 5:54-59.
4. Bajpai M et al. (1996) Roles of cytochrome P450-2C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin and to its major metabolite. Drug Metab. Dispos. 21:1401-1403.
5. http://www.imm.ki.se/CYPalleles/
6. Rost S et al. (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537-541.
7. Li T et al. (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427: 541-544.
8. Haining RL et al. (1996) Allelic variants of human cytochrome P450 2C9: Baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys. 333:447-58.
9. Lee CR et al. (2002) Cytochrome P450-2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12: 251-263.
10. Yuan HY et al. (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum MolGen 14:1745-1751.
11. Rieder MJ et al. (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. NEJM 352:2285-2293.
12. Loebstein R et al., (2006) A novel genetic marker of warfarin resistance. Blood Nov 16; [Epub ahead of print].

Specimen Requirements:
Two 5-10 ml tubes of anticoagulated blood. The preferred anticoagulant is EDTA (lavendar top tubes), ACD (yellow top) tubes are also accepted.

Shipping: Send at room temperature.

Turnaround Time: 24-48 hours

CPT Codes: 83891, 83892, 83894, 83898, 83900, 83901x5, 83912, 83914x2

Requisition and Consent Form: Warfarin Requisition and Consent [PDF]