Author(s): Kyung E Lee aff1 aff2 , Byung C Chang aff3 , Sunny Park aff1 , Hye S Gwak [*] aff1
8q24; c-Myc ; transcription factor; VKORC1 ; warfarin
Warfarin is the most commonly prescribed oral anticoagulant for the prevention of venous thromboembolism and systemic embolism in patients with prosthetic heart valves or atrial fibrillation. Due to its narrow therapeutic index and large interindividual and interethnic differences in dose requirements, the management of therapy is problematic. Numerous factors have been shown to affect the dose requirements for warfarin including age, weight, ethnicity, diet, concomitant medications and genetics [1,2 ]. VKORC1 and CYP2C9 genes are two genes known to play a critical role in the variability in warfarin doses due to their associations with pharmacodynamics and pharmacokinetics of warfarin [3-5 ].
Warfarin produces its anticoagulant effects by interfering with the cyclic interconversion of vitamin K and vitamin K epoxide, therefore, variations in VKORC1 cause clotting factor deficiencies. Warfarin exists as a racemic mixture of two optically active isomers, the R and S enantiomers. The S enantiomer of warfarin is three to five-times more potent than the R form, and polymorphisms in CYP2C9 , the primary enzyme of (S)-warfarin metabolism, result in a large variability in warfarin pharmacokinetics [5 ].
Recently, a single nucleotide polymorphism of a new gene, CYP4F2 (rs2108622), was reported to have a significant relationship with the stable warfarin dose [6,7 ]. CYP4F2 is primarily responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid, which is a potent vasoconstrictor of cerebral arteries. Moreover, CYP4F2 can hydroxylate the vitamin K phytyl side chain interfering with vitamin K recycling [8-10 ].
In an Asian population study, VKORC1 was found to be the most influential factor for warfarin dose variability [3 ]. Among the various SNPs of VKORC1 , -1173C [greater than] T (rs9934438) in intron 1 and -1639C [greater than] T (rs9923231) in the promoter region were substantial contributors affecting warfarin therapy. This polymorphism in rs9923231 alters a VKORC1 transcription factor binding site and carriers of the T allele have reduced amounts of VKORC1 mRNA [11 ].
c-Myc has been a topic of many studies related to its crucial role in diverse cancers as a multifaceted protein that regulates cell proliferation, differentiation and apoptosis [12-14 ]. However, only a few studies investigated its role associated with VKORC1. Moreover, there is no study on the association between c-Myc SNPs and warfarin therapy. A study showing c-Myc as a transcription factor targeting the element at VKORC1 revealed that the minor T allele of -1639C [greater than] T creates an Enhancer Box (E-box) motif, ACCTG, and c-Myc protein binds to the E-box elements [15 ]. There was a study demonstrating that there are enhancer elements located within the cancer-associated regions on chromosome 8q24 and that these elements can regulate c-Myc promoter activity in a reporter assay [ 16 ].
The purpose of this study was to determine whether polymorphisms in c-Myc , a transcription factor of VKORC1, contribute to the variability in stable warfarin doses. Moreover, effects of chromosome 8q24 SNPs on...