Warfarin Pharmacogenomics in Diverse Populations

Abstract

Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing.

Keywords: anticoagulation; diversity; pharmacogenomics; warfarin.

Figure 1:

Genes involved in warfarin metabolism and mechanism of action. CALU indicates calumenin; CYP2C18, cytochrome P450 family 2 subfamily C member 18; CYP2C9 indicates cytochrome P450 family 2 subfamily C member 9; CYP4F2, cytochrome P450 family 4 subfamily F member 2; GGCX, gamma-glutamyl carboxylase; NQO1, NAD(P)H quinone dehydrogenase 1; VKORC1, vitamin K epoxide reductase.

Figure 2:

Distribution of race/ethnicity in randomized prospective trials investigating genotype-guided warfarin dosing. Participant numbers are based on trials from Table S1 in Supplemental Materials. AA indicates African American.