Abstract 904: A Comparative Genomics Approach Identifies A Polymorphism In Calumenin As A Predictor Of High Warfarin Dose In African American Patients.
INTRO Warfarin is a widely used anticoagulant that is characterized by interindividual variability with important genetic influences. While single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1 predict warfarin dose, additional genetic variability is unexplained. Prior, limited studies of SNPs in calumenin (CALU, an inhibitor of vitamin K reductase and gamma carboxylase) and warfarin dose have yielded mixed results.
METHODS From a parent cohort of 900 patients on chronic warfarin we identified those outliers whose ratio of therapeutic to predicted warfarin dose (based on CYP2C9/VKORC1 genotype, body surface area (BSA), target INR, race, smoking, and medications) was either above the 90th (high-dose) or below the 10th (low-dose) percentiles. We sequenced 10 CALU regions (mean length 360 base pairs) that shared >90% conservation with mouse and rat orthologs. These regions covered all exons, 3′ and 5′ untranslated regions, and transcription factor binding sites. We compared the proportion of CALU SNPs between groups using a chi-square test and accounted for multiple comparisons with the false discovery rate (FDR).
RESULTS The low-dose group (n=53, mean daily dose 2.6±1.1 mg) required 55% of their predicted dose. The high-dose group (n=55, mean daily dose 12.7±8.3 mg) required 240% of their predicted dose. There were no differences in known determinants of warfarin dose (age, race, BSA, smoking, CYP2C9/VKORC1 genotype, and medications) between groups (p≥ .3). We identified 7 CALU SNPs (all in Hardy-Weinberg equilibrium): rs12538139, rs2290228, rs2290227, rs2307040, 25374C>T, rs339097, and rs1043550. Only rs339097, an intronic SNP, was significantly associated with the high-dose group (p= .01, FDR= .09). This allele was found only in African American patients (proportion with C allele in high-dose vs. low-dose 41% vs. 5%), with a minor allele frequency of 13%, consistent with HapMap results.
CONCLUSIONS This is the first CALU association study to employ a comparative genomics approach to SNP discovery. The association of rs339097, commonly polymorphic in African Americans, with the high-dose warfarin group may contribute to the higher warfarin dose in this population. Validation in a large, diverse cohort is necessary to confirm these results.