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Genetic Associations with Stable Warfarin Dose Requirements in Han Chinese Patients.

ABSTRACT
Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anti-coagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1 and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P=8×10-6 and 9×10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust=0.040 after Bonferroni correction). We discovered that, genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1 and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.