Sequence variation in COX-1 as it relates
to aspirin response has been investigated, with studies yielding inconsistent data.15, 16 Similar studies have been concluded with respect to SNPs that reside within the glycoprotein IIIa gene. These too have led to contradictory findings.17, 18 In a large meta-analysis, however, it was concluded that in healthy subjects the PlA1/A2 variant is associated with aspirin resistance,19 potentially implying that the effect of this SNP in inhibiting aspirin-mediated platelet inhibition may Inhibitors,research,lifescience,medical be reduced by the coadministration of drugs that are commonly prescribed in the context of CAD. Relatively common side effects to aspirin include gastrointestinal hemorrhage and aspirin-induced urticaria. Studies of DNA sequence variants that may alter the frequency of such endpoints have been investigated with variable Inhibitors,research,lifescience,medical results.19, 20 The Pharmacogenomics of Warfarin Warfarin is an effective anticoagulant and has been applied as thrombosis prophylaxis in settings including atrial fibrillation, venous thromboembolic disease, and metallic prosthetic valves. Warfarin acts by inhibiting vitamin K epoxide reductase (VKORC1),
the enzyme responsible Inhibitors,research,lifescience,medical for maintaining vitamin K in its reduced state. It is under this condition that its catalytic property is preserved; in its oxidized state, it is unable to catalyze the gamma-carboxylation of the vitamin-k dependent clotting factors (II, VII, IX, X) and proteins
C and S. Warfarin is metabolized Inhibitors,research,lifescience,medical by cytochrome P-450.22-24 Genome-wide association studies (GWAS) have this website subsequently identified rs2108622 in CYP4F2 to be associated with increased warfarin requirement; other SNPs have not met stringent genome-wide statistical thresholds.25-28 In retrospective studies, carriage of the two most common reduced-function CYP 2C9 variants, *2 (rs1799853) and *3 (rs1057910), predisposes one to an increased risk of an out-of-range international normalized ratio (INR), delay in the time-to-therapeutic INR, and increased bleeding.29, 30 Carriage of the A allele of VKORC131 and the T allele Inhibitors,research,lifescience,medical of CYP4F232 have been associated with both out-of-range INR and increased time-to-therapeutic PDK4 INR but not an increased propensity to bleed. Pharmacogenetic-centered modelling has been developed to predict warfarin requirement. Such modelling incorporates CYP P450 2C9 and VKORC1 genotype, smoking status, relevant medications, age, sex, and body mass index.33 The application of these algorithms has been investigated in several prospective studies demonstrating efficacy.34, 35 Standard dosing regimens have been compared with genotype-guided algorithms. Primary outcomes were the percent out-of-range INRs and time in the therapeutic range at 3 months.36 The combined genotype-guided prescription cohort demonstrated superior outcomes with respect to both primary endpoints—percent out-of-range INRs and time in the therapeutic range at 3 months.