Does Genotyping for Warfarin Sensitivity Save Lives? A Study of Individuals on Warfarin Who Died of Bleeding
Charlene Hellman, Clarissa Krinsky, Sarah Lathrop, Mohammad A Vasef. University of New Mexico, Albuquerque, NM
Background: Warfarin is an anticoagulant with a narrow therapeutic window and potentially catastrophic consequences outside of that window, such as stroke, myocardial infarction, or intracerebral hemorrhage. Establishing an appropriate dose is challenging due to interindividual variability according to genetics, body size, age, and sex.
Two genes predict optimal warfarin dose. First, cytochrome P450 enzyme 2C9 (CYP2C9) metabolizes warfarin. Variants of CYP2C9, CYP2C9 *2 and CYP2C9 *3, reduce warfarin clearance. Second, vitamin K epoxide reductase complex (VKORC1) recycles vitamin K needed for clotting factors, and is the pharmacologic target of warfarin. Although it is well established that CYP2C9 and VKORC1 alleles account for about one third of interindividual dose variability, data comparing clinical outcomes using genotype guided dosing versus standard dosing is scant. Most studies report a primary endpoint of percent INR values outside the target range because serious bleeding events are rare, thus difficult to measure.
Design: Our aim was to determine the frequency of CYP2C9 and VKORC1 variant alleles in people who died of bleeding or related complications while taking warfarin. Autopsy files at the medical investigator's office were searched and 82 subjects were identified. DNA was extracted from available specimens. Portions of CYP2C9 and VKORC1 genes containing relevant polymorphisms were amplified by PCR. Amplicons were analyzed by high resolution melting, and genotypes were determined by comparing subject melting curves to known controls. Frequencies of alleles were compared to those in the general population, matched for race, as published in medical literature.
Results: 82 subjects were genotyped, including 59 non-Hispanic white and 19 Hispanic white decedents. The frequency of CYP2C9 *2 was significantly higher in both groups than in the general population (non-Hispanic, 0.45 versus 0.16, p = 3.3 x10-14; Hispanic, 0.28 versus 0.08, p = 0.0021). The frequency of CYP2C9 *3 was not different. The frequency of the VKORC1 warfarin sensitive haplotype trended higher in non-Hispanic whites (0.45 versus 0.38, p = 0.17) and achieved significance in Hispanic whites (0.72 versus 0.45, p = 0.001).
Conclusions: Variant alleles conferring enhanced sensitivity to warfarin are overrepresented in the sample population compared to the general population. Therefore, warfarin sensitive genotypes are associated with increased risk of death in people taking warfarin. Whether genotyping would have prevented deaths cannot be determined by the present study, and warrants further investigation.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 5, Monday Morning