Identification of two novel genes SLC15A2 and SLCO1B3 associated with maintenance dose variability of warfarin in a Chinese population

Abstract

Warfarin is a commonly prescribed and effective oral anticoagulant. Genetic polymorphisms associated with warfarin metabolism and sensitivity have been implicated in the wide inter-individual dose variation that is observed. Several algorithms integrating patients’ clinical characteristics and genetic polymorphism information have been explored to predict warfarin dose. However, most of these algorithms could explain only over half of the variation in a warfarin maintenance dose, suggesting that additional genetic factors may exist and need to be identified. Here, a drug absorption, distribution, metabolism and excretion (ADME) Core Panel Kit-based pharmacogenetic study was performed to screen for warfarin dose-associated SNP sites in Han-Chinese population patients taking warfarin therapy, and the screen was followed by pyrosequencing-based validation. Finally, we confirmed that the common variant rs9923231 in VKORC1 and two novel genes, SLC15A2 (rs1143671 and rs1143672) and SLCO1B3 (rs4149117 and rs7311358), are associated with the warfarin maintenance dose. As has been shown for those carriers with the variant rs9923231 in VKORC1, it was suggested that those subjects with homozygous minor alleles in those four SNPs should take a lower warfarin dose than those carrying the wild type alleles. Together with the established predictor rs9923231 in VKORC1, those four novel variants on SLC15A2 and SLCO1B3 should be considered as useful biomarkers for warfarin dose adjustment in clinical practice in Han-Chinese populations.

Concordância entre bases de dados sobre interações medicamentosas entre varfarina e antimicrobianos: uma análise descritiva.

“…De modo geral, a ocorrência de IM depende, entre outros fatores, do metabolismo do paciente, da sua condição de saúde, da exposição aos medicamentos envolvidos, da idade, e também de outros fatores igualmente importantes, como a posologia prescrita, considerando horários de administração, dose e período de uso 28 . Para a varfarina, além destes fatores, devem ser considerados os polimorfismos genéticos que determinam o efeito 29 , alimentação e estado nutricional 30 .…”

Concordance rate amongst electronic databases regarded the information on potential drug interactions between warfarin and antimicrobials: a descriptive analysis

“…The occurrence of DDI depends on the patient's metabolism, health condition, age, and also other equally important factors, such as administration times, dose, and time of exposure [28]. Moreover, patients´ therapeutic response under warfarin treatment alone varies widely due to several factors, such as genetic polymorphisms [29], diet and nutritional status, age, liver health, and other drugs used, since warfarin interacts with a large number of drugs [30].…”

Organic Anion Transporter Gene Variants Associated With Plasma Exposure and Long‐Term Response to Atrasentan in Patients With Diabetic Kidney Disease

“…The literature search resulted in the selection of 12 SNPs within 9 genes encoding for the following membrane transporters, metabolizing enzymes or drug targets: OATP1A2 (rs4148978), 8 , 14 OATP1B1 (rs2306283 and rs4149056), 8 , 15 OATP1B3 (rs4149117), 8 , 16 OATP2B1 (rs2306168), 17 ABCB1 (rs1128503), 8 , 18 CYP3A4 (rs35599367), 6 , 19 CYP3A5 (rs776746), 7 UGT1A1 (rs4148323 and rs887829), 8 , 20 , 21 , 22 and EDN1 (rs9296344 and rs5370). 23 , 24 …”