Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics

Abstract

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 C>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0-1.6, 2.0-2.9, and 2.9-3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding.

Figures

Fig 1

Carrier prevalence of CYP2C9/VKORC1 polymorphisms in 92 Puerto Ricans: Eight CYP2C9 (five *1*2; three *1*3) and thirty-two VKORC1 only carriers (twenty-nine GA; three AA); twelve single CYP2C9 and single VKORC1 carriers (five *1*2/GA; six *1*3/GA; one *1*6/GA); three single CYP2C9 and double VKORC1 carriers (two *1*2/AA; one *1*3/AA). Thirty-seven non-carriers were found

Fig 2

Predicted mean decreases in warfarin dose (mg/day) in hypothetical individuals (55-yo, BMI=27, both genders) taken from a population with the same genotypic frequencies observed in Puerto Ricans. The hatched areas indicate ranges of predicted dose reductions based on a published algorithm. The upper and lower bars represents the reductions for male and female, respectively