Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR)

• Published in: Toxicology and applied pharmacology Vol. 309; pp. 37 - 43
• Main Authors: Pourgholi, Leyla, Goodarzynejad, Hamidreza, Mandegary, Ali, Ziaee, Shayan, Talasaz, Azita Hajhosseini, Jalali, Arash, Boroumand, Mohammadali
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-10-2016
• Subjects: 60 APPLIED LIFE SCIENCES; Aged; Anticoagulants - adverse effects; Bleeding; CHAIN REACTIONS; COMPUTERIZED TOMOGRAPHY; Cross-Sectional Studies; Cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9); CYTOCHROMES; Female; GENOTYPE; HAZARDS; Hemorrhage - chemically induced; Humans; International Normalized Ratio; International normalized ratio (INR); Iran; Male; Middle Aged; NQO1; PATIENTS; POLYMERASE CHAIN REACTION; POLYMERASES; Polymorphism; Polymorphism, Single Nucleotide; POLYPEPTIDES; RFLPS; Warfarin; Warfarin - adverse effects; NQO1; Warfarin; Genotype; Cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9); Bleeding; International normalized ratio (INR); Polymorphism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.08.026

Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients.
A total of 552 warfarin treated patients who maintained on a target INR level of 2.0–3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP).
Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P=0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P=0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events.
The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations.
•NQO1 C609T variant is associated with warfarin induced bleeding at therapeutic INR.•Haplotypes of CYP2C9 (1*2 or 1*3) are also associated with bleeding events.•VKORC1, Factor VII, and EPHX1 genotypes were not associated with bleeding risk.