Genomic Association Study of Warfarin in Caribbean Hispanics

INTRODUCTION: Despite the advent of the new direct oral anticoagulants, warfarin continues to be a mainstay therapy in thromboembolic disorders. Warfarin dosing requirements are highly variable and it may lead to serious... [ view full abstract ]

INTRODUCTION: Despite the advent of the new direct oral anticoagulants, warfarin continues to be a mainstay therapy in thromboembolic disorders. Warfarin dosing requirements are highly variable and it may lead to serious adverse events. Existing genotype-driven algorithms account for ∼50% of this variance, but they do not perform as well in populations other than Caucasians because some ethno-specific alleles are overlooked. The impact of pharmacogenomics on dose requirements for Hispanics is unknown due to their underrepresentation in clinical trials. This study was aimed to identify genetic polymorphisms that can explain variability in warfarin dosing among Caribbean Hispanics. METHODS: A case-control pharmacogenetic association study was conducted in 275 Puerto Rican patients on warfarin, using the Extreme Discordant Phenotype approach. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET®-Plus Array were performed. RESULTS: An admixture-adjusted pharmacogenetic model that explained more than two-thirds of observed variance in stable warfarin dose in Caribbean Hispanics was developed (Fig.1). CYP4F2*3 and NQO1*2 variants were independently associated with a 17 and 10% increase of the dose per allele, respectively. On the other hand, the admixture index decreases the dose by 7%. The African-related rare CYP2C9*8 allele explained 31% decrease of the dose. The genomic diversity of Puerto Ricans is highlighted by the presence of 11 major CYP2C9 haplotypes (Fig.2). The CYP2C9 rs2860905 variant showed stronger association with warfarin sensitivity than common CYP2C9*2 and *3 alleles (Fig.3). Incorporation of rs2860905 in a model that also includes additional genetics (VKORC1-1639G>A; CYP2C9rs1856908; ABCB1c.IVS9-44A>G; CES2c.269-965A>G) and non-genetic factors showed better prediction of warfarin dose requirements. The genetic background of participants showed a tri-hybrid admixture pattern. DISCUSSION: Although our findings need further replication, our study contributes to the field by identifying novel genetic variants that increase predictability of warfarin dosing among Caribbean Hispanics. We described variants in CYP2C9 (e.g., rs2860905) and other pharmacogenes (e.g., NQO1, CES2) that were found for the first-time ever to be significantly associated with warfarin dose requirements in a cohort of Caribbean Hispanics. We concluded that admixture and ethno-specific alleles are both clinically relevant predictors for algorithmically computed warfarin doses in Caribbean Hispanics.