title: Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR).
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran; Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, P.O. Box 7616911319, Kerman, Iran.
authors: Leyla
authors: L
authors: Pourgholi
authors: Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran.
authors: Hamidreza
authors: H
authors: Goodarzynejad
authors: Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, P.O. Box 7616911319, Kerman, Iran; Gastroenterology and Hepatology Research Center, Afzalipour's Hospital, Imam Highway, P.O. Box 7616913911, Kerman, Iran.
authors: Ali
authors: A
authors: Mandegary
authors: Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran.
authors: Shayan
authors: S
authors: Ziaee
authors: Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran; Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences.
authors: Azita Hajhosseini
authors: AH
authors: Talasaz
authors: Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran.
authors: Arash
authors: A
authors: Jalali
authors: Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran. Electronic address: maboroumand@yahoo.com.
authors: Mohammadali
authors: M
authors: Boroumand
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D019934:International Normalized Ratio; D007492:Iran; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: Bleeding; Cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9); Genotype; International normalized ratio (INR); NQO1; Polymorphism; Warfarin