Warfarin Pharmacogenomics in a Hispanic Population: A Candidate SNP Study

Abstract

Background: Warfarin remains one of the most widely prescribed anticoagulants but is also a leading cause of adverse drug reactions. Genotype-guided warfarin dosing algorithms enable accurate dose estimation, potentially leading to improved safety and efficacy. However, genotype-guided dosing algorithms were developed primarily in populations of European descent and limited data are available regarding single nucleotide polymorphisms (SNPs) that significantly influence warfarin dose in Hispanic populations. Research Aim: The objective of this study was to determine whether clinical factors and SNPs previously associated with stable warfarin dose variability in populations of European and Hispanic descent accurately predicted warfarin stable dose in a Hispanic population. Study Design: Self-reported Hispanic and Latino patients on stable warfarin dose (defined as the same dose for at least two clinic visits separated by at least two weeks) were recruited. Methods: Candidate SNPs, including CYP2C9*2/*3, VKORC1-1639G>A, CYP4F2*3, and NQO1*2, were genotyped and clinical data were collected using a survey and the electronic medical record. Stepwise linear regression was performed to determine variables that significantly predicted square root of weekly warfarin dose. Results: A total of 76 patients of primarily Mexican American ancestry participated. All SNPs were within Hardy-Weinberg Equilibrium. The final stepwise regression model incorporated six variables, which explained 71% of the variability in warfarin weekly dose requirements. Significant predictors included weight (R2=0.287, p<0.0001), age (R2=0.143, p<0.0001), amiodarone use (R2=0.067, p=0.0005), and prior stroke (R2=0.025, p=0.02). Significant SNPs included VKORC1-1639A (R2=0.152, p<0.0001), and CYP2C9*2/*3 (R2=0.032, p=0.02). CYP4F2*3 and NQO1*2 did not significantly impact warfarin dose requirements despite previously published associations in Hispanic populations. Conclusion: These findings suggest that clinical and genetic predictors of warfarin weekly dose requirements are similar among populations of European descent and Hispanic populations with Mexican American ancestry. These results require replication and validation in independent cohorts with similar ethnicity, but advance our understanding of influences on warfarin dose variability among different race/ethnic groups.