VL is a 62 yo Caucasian female who is now starting anticoagulation with warfarin for onset of atrial fibrillation. She is a Type 2 diabetic with hypertension and hyperlipidemia and is taking:

• Metformin 500 mg BID with meals
• Lisinopril 10 mg daily
• Atorvastatin 20 mg daily

VL does not smoke or drink and is advised to start a heart-healthy diet including increased salad intake. Her baseline INR is 1.0 with a goal of 2.5. Her genotype profile is:

• CYP2C9*3/*3
• VKORC1-1639A/A

Warfarin has a narrow therapeutic window with a significant risk of bleeding; PGx testing can be used to affect medication dosing. The CYP2C9 and VKORC1 polymorphisms can affect warfarin dosing. However, not all patients with polymorphisms in CYP2C9 or VKORC1 will have a serious bleeding event; those without any polymorphism may still be susceptible to having a bleeding event due to clinical, nongenetic factors.

The CYP2C9 alleles affect the metabolism of warfarin.

The VKORC1 1173 C>T or VKORC1-1639 G>A alleles affect the formation of vitamin K-dependent clotting factors.

Dosing Considerations:

• Patients with CYP2C9*2 or CYP2C9*3 alleles may have decreased CYP2C9 activities by 50% to 90%, requiring lower warfarin doses.
• Haplotype A from VKORC1 SNPs is associated with lower warfarin dose requirements; VKORC1A/A genotype generally requires a lower weekly warfarin dose of 32%.
• Haplotype B is associated with higher warfarin dose requirements; Haplotype B/B generally requires an increased weekly warfarin dose of 35%.
• It appears from numerous reports that the VKORC1 allele is of greater importance in determining the warfarin maintenance dose than is the CYP2C9 genotype.

Dosing data from a published table extracted and presented below may be of assistance:

Next week, we will look at some resources available to support your PGx practice.

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