BACKGROUND: Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter-individual variation in warfarin response. OBJECTIVE: We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target. METHODS: The sample consisted of 93 European-American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed. RESULTS: Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173. CONCLUSIONS: These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions.
BACKGROUND:Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter-individual variation in warfarin response. OBJECTIVE: We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target. METHODS: The sample consisted of 93 European-American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed. RESULTS: Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173. CONCLUSIONS: These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions.
Authors: L Poller; C R Shiach; P K MacCallum; A M Johansen; A M Münster; A Magalhães; J Jespersen Journal: Lancet Date: 1998-11-07 Impact factor: 79.321
Authors: Simone Rost; Andreas Fregin; Vytautas Ivaskevicius; Ernst Conzelmann; Konstanze Hörtnagel; Hans-Joachim Pelz; Knut Lappegard; Erhard Seifried; Inge Scharrer; Edward G D Tuddenham; Clemens R Müller; Tim M Strom; Johannes Oldenburg Journal: Nature Date: 2004-02-05 Impact factor: 49.962
Authors: Ahmet Kocael; Allison Pınar Eronat; Mete Bora Tüzüner; Ahmet Ekmekçi; Ahmet Lütfullah Orhan; İbrahim İkizceli; Hülya Yılmaz-Aydoğan; Oğuz Öztürk Journal: Mol Biol Rep Date: 2019-02-02 Impact factor: 2.316
Authors: Mohi Iqbal Mohammed Abdul; Xuemin Jiang; Kenneth M Williams; Richard O Day; Basil D Roufogalis; Winston S Liauw; Hongmei Xu; Anita Matthias; Reginald P Lehmann; Andrew J McLachlan Journal: Br J Clin Pharmacol Date: 2010-05 Impact factor: 4.335