Warfarin Pharmacogenetics: Challenges and Opportunities for Clinical Translation

Candidate gene studies The recognition of genetic regulation of warfarin response has stimulated efforts aimed at quantifying this influence. The bulk of the evidence supports the influence of single nucleotide polymorphisms (SNPS) in two genes; Cytochrome P450 2C9 (CYP2C9; codes for the main enzyme involved in warfarin metabolism) and Vitamin K epoxide reductase complex1 (VKORC1; encodes the vitamin K–epoxide reductase protein, the target enzyme of warfarin). The influence of SNPs in CYP2C9 and VKORC1 on warfarin dose has been extensively assessed and reviewed (Wadelius et al., 2007, 2009; Limdi and Veenstra, 2008; Cavallari and Limdi, 2009; Klein et al., 2009). This evidence provided the basis for the recent warfarin package insert update by the United States Food and Drug Administration (FDA). Moreover clinical algorithms that can enable dose prediction incorporating patient-specific genetic and clinical information have been developed and are freely available. Gage et al. (2008) have developed a dosing algorithm based on clinical and demographic factors (body surface area, age, target INR, amiodarone use, smoker status, race, current thrombosis) along with CYP2C9 (*2, *3, *5, and *6), VKORC1 (−1639/3673G>A), GGCX (rs11676382), and CYP4F2 (V433M) polymorphisms. The algorithm is freely available at www. warfarindosing.org and allows calculation of warfarin dose based on clinical and demographic factors alone (if genotype is not available). Incorporation of novel and potentially important genetic variants (such Despite its wide use over six decades, warfarin therapy remains challenging due its narrow therapeutic index. The multitude of factors interacting with warfarin makes it difficult to maintain anticoagulation within the target International Normalized Ratio (INR) range (Ageno et al., 2012). Even within this range the dose requirements vary as much as 20-fold between patients. Deviations in INR control with frequent over and under-anticoagulation are common (Chiquette et al., 1998; Chamberlain et al., 2001; Ansell et al., 2007), are associated with poor outcomes with underanticoagulation (increasing the risk of thrombosis) and over-anticoagulation (increasing the risk of serious or fatal hemorrhage), demanding that anticoagulation control be tightly regulated (Hylek and Singer, 1994; Hylek et al., 1996, 2000; Hylek, 2003; Wittkowsky, 2004; Wittkowsky and Devine, 2004; Hylek and Rose, 2009). These adverse outcomes have relegated warfarin to the “top 10 drugs” for adverse drugrelated hospitalizations in the US (Budnitz et al., 2007, 2011). Between 2007 and 2009 warfarin accounted for 33% of drug-related hospitalizations for adverse events in the US (Budnitz et al., 2011). The risk for hemorrhage is particularly elevated when the INR exceeds four, as well as during the initial months of therapy. Therefore it is critical to achieve a safe and effective level of anticoagulation for patients starting warfarin. Current guidelines for initiation of therapy provided by the American College of Chest Physicians (ACCP) allow flexibility in selecting a starting dose of warfarin, suggesting 5–10 mg. Although the ACCP guidelines recommend lower (2.5–5 mg) doses recognizing the influence of age, comorbidities, nutritional status, and drug as CYP2C9*8) can further improve dosing prediction in African American patients (Cavallari et al., 2010; Cavallari and Perera, 2012). As demonstrated by multiple studies, including the work of the International Warfarin pharmacogenetics Consortium (IWPC), dosing based on clinical/demographic factors alone improves prediction of stable therapeutic dose of warfarin (compared to the one-size-fits-all 5 mg/ day dose), specifically in patients that need ≥7 mg/day or ≤3 mg/day. Furthermore inclusion of CYP2C9 and VKORC1 provide a substantial gain in improvement of dose prediction in 46% of patients (Klein et al., 2009). The www.warfarindosing.org also allows the user to compute the estimated dose requirements based on the IWPC algorithm. Both pharmacogenetic algorithms (Gage et al., 2008; Klein et al., 2009) require detailed mathematical calculations to predict warfarin dose. A simpler alternative is to refer to the genotype-stratified warfarin dose table recently added to the warfarin label by the U.S. FDA. Although pharmacogenetic algorithms are most accurate, the genotype-stratified warfarin dose table provides a more accurate dose prediction than empiric dosing (Finkelman et al., 2011). The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network has developed guidelines to assist clinicians in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. These guidelines are published (Johnson et al., 2011) and