Genotype and risk of major bleeding during warfarin treatment

Abstract

Aim: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy.

Materials & methods: Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy.

Results: CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04).

Conclusion: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.

Keywords: CYP2C9; CYP4F2; VKORC1; pharmacogenetics; risk of major bleeding; warfarin.

Figure 1. Algorithm used to identify cases and controls for the final analysis

^†517 potential cases and 839 potential controls were reviewed to identify 277 cases and 307 controls frequency matched for age, sex, race and year of hospital admission who met the case and control definition. ^‡Not genotyped because they had either opted-out or had inadequate DNA concentration for genotyping. EMR: Electronic medical record; ICD-9: International Classification of Diseases, 9th Revision, Clinical Modification.

Figure 2. Major bleeding risk

Genotype and risk of major bleeding (A) during warfarin therapy and (B) after 30 days of warfarin therapy. Adjusted for age, sex, race, body surface area, log[time on warfarin], VKORC1, CYP2C9*2, CYP2C9*3, CYP4F2 genotype, number of warfarin inhibitors, number of warfarin potentiators, use of antiplatelet agents and nonsteroidal anti-inflammatory drugs, previous bleeding without warfarin and atrial fibrillation and venous thromboembolism as indication for warfarin. CYP2C9*2+*3 represents the combined genotype information for CYP2C9*2 and CYP2C9*3 in an additive model (0 allele = 0, 1 allele = 1 and 2 allele = 2; e.g., *1/*1 = 0, *1/*2 = 1, *1/*3 = 1, *2/*2 = 2; *2/*3 = 2). OR: Odds ratio.