Abstract
Background/Aims Studies evaluating newly initiated warfarin patients in anticoagulation clinics show that polymorphisms in CYP2C9, VKORC1, and CYP4F2 influence dose requirements, and CYP2C9 variants have increased risk of major bleeding side effects. However, these findings may not be applicable to long-term warfarin users or non-specialist care settings. Within this context, our objective was to evaluate the association between CYP2C9*2 and *3, VKORC1 1173, and CYP4F2*3 variants and major bleeding in long-term warfarin users in a community setting.
Methods We used a case-control design and recruited patients from Group Health (GH). Cases experienced a major bleeding event while receiving warfarin. Controls received warfarin on a randomly assigned index date, and had no major bleeding in the prior year. We identified major bleeding with an ICD-9 algorithm, and validated events with chart review. We obtained covariates from GH automated databases and a self-report survey. Our primary analysis used logistic regression to estimate the major bleeding odds ratio (OR) for variants vs. wild type patients. We also conducted an exploratory analysis to estimate the major bleeding OR for patients with variable vs. constant dietary vitamin K intake, stratified by genetic status.
Results We enrolled 265 cases and 305 controls with an average of 3.4 and 3.7 years of warfarin use at the index date, respectively. In our primary analysis, the CYP4F2 variant was independently associated with decreased major bleeding risk (OR: 0.62, 0.43–0.91), and CYP2C9 and VKORC1 had null associations. In our exploratory analysis, CYP4F2 wild type patients demonstrated a trend toward increased major bleeding risk with variable vs. constant vitamin K intake (OR = 1.18, 0.64–2.16), while there was a null association in CYP4F2 variants
Conclusions In the largest study of warfarin pharmacogenomics and major bleeding to date, we found that a common CYP4F2 variant is associated with a 38% reduction in risk of major bleeding. In contrast, CYP2C9 and VKORC1 variants demonstrated null associations. Our findings may reflect a gene-drug-environment interaction between CYP4F2*3, warfarin, and dietary vitamin K intake. Collectively, our findings expand understanding of genetic risk factors for major bleeding in warfarin therapy, and can potentially inform dosing and monitoring practices pending validation in independent cohorts.
