Common P-glycoprotein (ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events

Abstract

Graphical abstract Highlights • An evaluation of the association of the common ABCB1 polymorphisms and risk of bleeding in rivaroxaban-treated patients was performed • The four common ABCB1 polymorphisms did not affect the risk of bleeding in rivaroxaban-treated patients of European descent • Consistent results were observed based on raw data and fully adjusted data, in the analysis based on the “load” of variant alleles across the four polymorphisms, haplotype-based analysis and analysis based on the combination of genotypes at the investigated polymorphisms IntroductionConsidering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. Materials and methodsWe report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the “load” of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. ResultsThere were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. ConclusionsThe evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.