Dataset Information

Effects of Polymorphisms in Myc-Related Genes on Bleeding Complications in Patients with Stable Warfarin Responses.

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 (? 2=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.

SUBMITTER: Yee J

PROVIDER: S-EPMC6739803 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Effects of Polymorphisms in Myc-Related Genes on Bleeding Complications in Patients with Stable Warfarin Responses.

Yee Jeong J Kim Woorim W Chang Byung Chul BC Chung Jee Eun JE Lee Kyung Eun KE Gwak Hye Sun HS

Cardiovascular therapeutics 20190508

<h4>Objectives</h4>This study aimed to identify the possible effects of <i>Myc</i> 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.<h4>Methods</h4>Twenty-five single nucleotide polymorphisms were analyzed, including <i>VKORC1</i>, <i>CYP2C9</i>, <i>Myc</i>, and 8q24. Univariate and multivariate analyses were conducted to evaluate the associations between genetic polym ...[more]

PMID: 31772606

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Project description:This study aimed to investigate the effects of genetic variants and haplotypes in the renin-angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02-0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8-14.1) and 3.2-fold (95% CI 1.1-8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)-linear kernel, and SVM-radial kernel models were 0.732 (0.694-0.771), 0.741 (0.612-0.870), 0.723 (0.589-0.857), 0.673 (0.517-0.828), and 0.680 (0.528-0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1-46.7) increased risk of bleeding, compared to the 25-75th percentile group, respectively. This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding.

Project description:Bleeding events are the major obstacle to the widespread use of warfarin for secondary stroke prevention. Previous studies have not examined the use of risk stratification scores to estimate lifetime bleeding risk associated with warfarin treatment in a population-based setting. The purpose of this study is to determine the lifetime risk of bleeding events in ischemic stroke patients with atrial fibrillation (AF) undergoing warfarin treatment in a population-based cohort and to evaluate the use of bleeding risk scores to identify patients at high risk for lifetime bleeding events.The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with AF undergoing warfarin treatment for secondary stroke prevention from 1980 to 1994. Medical information for patients seen at Mayo Clinic and at Olmsted Medical Center was used to retrospectively risk-stratify stroke patients according to bleeding risk scores (including the HAS-BLED and HEMORR2HAGES scores) before warfarin initiation. These scores were reassessed 1 and 5 years later and compared with lifetime bleeding events.One hundred patients (mean age, 79.3 years; 68% women) were studied. Ninety-nine patients were observed until death. Major bleeding events occurred in 41 patients at a median of 19 months after warfarin initiation. Patients with a history of hemorrhage before warfarin treatment were more likely to develop major hemorrhage (15% versus 3%, P = .04). Patients with baseline HAS-BLED scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (53% versus 7%, P < .01), whereas those with HEMORR2HAGES scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (52% versus 16%, P = .03). Patients with an increase in the HAS-BLED and HEMORR2HAGES scores during follow-up had a higher remaining lifetime risk of major bleeding events compared with those with no change.Our findings indicate high lifetime bleeding risk associated with warfarin treatment for patients with ischemic stroke. Risk stratification scores are useful to identify patients at high risk of developing bleeding complications and should be recalculated at regular intervals to evaluate the bleeding risk in anticoagulated patients with ischemic stroke.

Project description:Purpose: GATA4 and GATA6 are known to have potential roles in vascular regulation by affecting vascular smooth muscle cell differentiation and atrial natriuretic peptide levels. The aim of this retrospective study was to investigate the associations between GATA4 and GATA6 polymorphisms and bleeding complication risk at a therapeutic international normalized ratio (INR) in patients with mechanical heart valves. Patients and methods: Study patients were included from the Ewha-Severance Treatment (EAST) Group of Warfarin. It consisted of 229 patients who received warfarin therapy after undergoing mechanical heart valve replacement and maintained a stable INR (INR of 2.0-3.0 for at least three consecutive times). Twenty single-nucleotide polymorphisms including VKORC1, CYP2C9, GATA4, and GATA6 were analyzed. Multivariate logistic regression analysis was employed to investigate the independent risk factors for bleeding complications. To evaluate the potential clinical value of genotyping for preventing bleeding complications in patients with high-risk genotype, the number needed to genotype (NNG) was also calculated. Results: One hundred forty-two patients were included in this study, 21 of whom had bleeding complications. After adjusting covariates, TT genotype carriers of rs13273672 in GATA4 and CC genotype carriers of rs10454095 in GATA6 showed 5.0- (95% CI, 1.6-15.7) and 3.1-fold (95% CI, 1.1-8.7) higher bleeding complications than carriers of C allele and T allele, respectively. NNG for preventing one patient from experiencing bleeding complications in patients with TT genotype of rs13273672 and CC genotype of rs10454095 was 22.2 and 17.5, respectively. Patients with both TT genotype in rs13273672 and CC genotype in rs10454095 showed 8.7-fold (95% CI, 1.7-46.1) higher bleeding complications than those with other genotypes. NNG in patients having both TT genotype in rs13273672 and CC genotype in rs10454095 was calculated to be 40.0. Conclusions: This study showed that GATA4 and GATA6 gene polymorphisms could affect bleeding complications during warfarin treatment in patients with mechanical heart valves.

Project description:In patients with acute liver failure (ALF), elevated prothrombin time and thrombocytopenia can fuel a perception of a bleeding tendency. However, the incidence, site, risk factors, and clinical significance of bleeding complications have not been quantified in a large cohort of patients with ALF. We studied 1,770 adult patients enrolled in the ALF Study Group Registry between 1998 and 2016. Bleeding complications and blood component transfusions were collected for 7 days after admission. The relationship of bleeding complications to 21-day mortality was assessed. Despite a median international normalized ratio of 2.7 and platelet count of 96 × 109 /L on admission, bleeding complications were observed in only 187 patients (11%), including 173 spontaneous and 22 postprocedural bleeding episodes. Eighty-four percent of spontaneous bleeding episodes were from an upper gastrointestinal source and rarely resulted in red blood cell transfusion. Twenty patients experienced an intracranial bleed; half of these occurred spontaneously and half after intracranial pressure monitor placement, and this was the proximate cause of death in 20% and 50%, respectively. Bleeders and patients who received red blood cell transfusions were more acutely ill from extrahepatic organ system failure but not from hepatocellular failure. Consistent with this observation, bleeding complications were associated with lower platelet counts but not higher international normalized ratio. Transfusion of any blood component was associated with nearly 2-fold increased death or need for liver transplantation at day 21, but bleeding complications were the proximate cause of death in only 5% of cases. CONCLUSIONS:Despite a perceived bleeding diathesis, clinically significant bleeding is uncommon in patients with ALF; bleeding complications in patients with ALF are markers of severe systemic inflammation rather than of coagulopathy and so portend a poor prognosis. (Hepatology 2018;67:1931-1942).

Dataset Information

Effects of Polymorphisms in Myc-Related Genes on Bleeding Complications in Patients with Stable Warfarin Responses.

Publications

Effects of Polymorphisms in Myc-Related Genes on Bleeding Complications in Patients with Stable Warfarin Responses.

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