Abstract
Objectives This study aimed to identify the possible effects of Myc and 8q24 polymorphisms on bleeding complications in patients who maintained international normalized ratio (INR) of 2.0-3.0 with warfarin therapy after cardiac valve replacement. Methods Twenty-five single nucleotide polymorphisms were analyzed, including VKORC1, CYP2C9, Myc, and 8q24. Univariate and multivariate analyses were conducted to evaluate the associations between genetic polymorphisms and bleeding complications. Attributable risk and the number needed to genotype (NNG) were also calculated to evaluate the potential clinical value of genotyping. Results We included 142 patients, among whom 21 experienced bleeding complications. Multivariate models showed that patients carrying the CC genotype of rs6983561 and the A allele of rs13281615 at 8q24 had 27.6- and 10.0-fold higher bleeding complications, compared with patients with the A allele and the GG genotype, respectively. For rs6983561, the attributable risk and NNG were 96.4% and 36.8, respectively, whereas, for rs13281615, the attributable risk and NNG were 90.0% and 8.3, respectively. Atrial fibrillation was associated with a 5.5-fold increased risk of bleeding complications. The AUROC value was 0.761 (95% CI 0.659-0.863, p<0.001), and the Hosmer–Lemeshow test showed that the fitness of the multivariate analysis model was satisfactory (χ2=0.846; 3 degrees of freedom; p=0.838). Conclusions Bleeding complications during warfarin therapy were associated with 8q24 polymorphisms and atrial fibrillation in patients with mechanical heart valves.
Highlights
Warfarin is a widely used anticoagulant, and its effectiveness is well established, mainly for preventing and treating atrial fibrillation, ischemic stroke, deep vein thrombosis, and pulmonary embolism [1, 2]
Even though an elevated international normalized ratio (INR) is correlated with an increased warfarin-associated bleeding risk, bleeding complications can be seen in patients at a therapeutic INR [5]
To select single nucleotide polymorphisms (SNPs) of Myc and 8q24 that might be associated with warfarin-related bleeding, genetic information concerning Myc and 8q24 was obtained from the PharmGKB database, Haploreg 4.1, and the National Center for Biotechnology (NCBI) SNP Database, as well as previous studies [10, 13,14,15,16,17,18]
Summary
Warfarin is a widely used anticoagulant, and its effectiveness is well established, mainly for preventing and treating atrial fibrillation, ischemic stroke, deep vein thrombosis, and pulmonary embolism [1, 2]. Warfarin has several shortcomings, such as a narrow therapeutic range and wide inter- and intra-individual variability. Warfarin administration requires close monitoring, using the international normalized ratio (INR) [4]. The most common adverse effect of warfarin is bleeding. Even though an elevated INR is correlated with an increased warfarin-associated bleeding risk, bleeding complications can be seen in patients at a therapeutic INR [5]. Some studies have demonstrated that—in addition to a high INR—age, hypertension, and concomitant aspirin use were patient-related risk factors for bleeding complications [5, 6]
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