Genome-Wide Association Study Identifies Copy Number Variants Associated with Warfarin Dose Response and Risk of Venous Thromboembolism in African Americans.

The anticoagulant warfarin is commonly used to control and prevent thrombotic disorders such as venous thromboembolism (VTE), which disproportionately afflicts African Americans (AAs). Despite the importance of copy number variants (CNVs), few studies have focused on characterizing and understanding their role in drug response and disease risk among AAs. In this study, we conduct the first genome-wide analysis of CNVs to more comprehensively account for the contribution of genetic variation in warfarin dose requirement and VTE risk among AAs. We used hidden Markov models to detect CNVs from high-throughput SNP arrays for 340 AA participants in the International Warfarin Pharmacogenetics Consortium. We identified 11,570 CNVs resulting in 2,038 copy number variable regions (CNVRs) and found three CNVRs associated with warfarin dose requirement and three CNVRs associated with VTE risk in AAs. CNVRs 1q31.2del and 6q14.1del were associated with increased warfarin dose requirement (β=11.18 and 4.94, respectively; P emp =<0.002); CNVR 19p13.31del was associated with decreased warfarin dose requirement (β=-1.41, P emp =0.0004); CNVRs (2p22.1del and 5q35.1-q35.2del) were found to be associated with increased risk of VTE (ORs = 1.88 and 14.9 respectively; P emp ≤0.02); and CNVR 10q26.12del was associated with a decreased risk of VTE (OR 0.6; P emp =0.05). Modelling of the 10q26.12del in HepG2 cells revealed that this deletion results in decreased fibrinogen gene expression, decreased fibrinogen and WDR11 protein levels, and decreased secretion of fibrinogen into the extracellular matrix. We found robust evidence that CNVRs could contribute to warfarin dose requirement and risk of VTE in AAs and for 10q26.3del describe a possible pathogenic mechanism.