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APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR.

ABSTRACT: The purpose of this study was to investigate influence of gene polymorphisms of APOB and APOE on risk of bleeding complications at therapeutic INR, during warfarin treatment in Korean patients with mechanical cardiac valves. The study included 142 patients from the EwhA-Severance Treatment Group (EAST) of Warfarin. A total of 12 SNPs was investigated. Five SNPs of APOB (c.13013G>A, c.1853C>T, c.1594C>T, c.293C>T, and c.7545C>T) and five SNPs of APOE (g.4798T>G, g.6406G>A, g.10413T>C, c.388T>C, and c.526C>T) were selected. In addition to selected SNPs, VKORC1 g.6399C>T, and CYP2C9 c.1075A>C, which were known to have significant effects on warfarin stable doses, were also included in the study. Two SNPs of APOB (c.293C>T and c.1853C>T) were associated with bleeding complications. T allele carriers of c.293C>T had 8.6 times (95% CI 2.9-25.5, p?T had 6.4 times (95% CI 2.3-17.9, p?T and c.293C>T were 0.771 and 0.802, respectively. Among demographic characteristics, age was the only significant factor. This study revealed that APOB was associated with bleeding complications in patients with warfarin treatment after mechanical cardiac valves.

SUBMITTER: Yee J

PROVIDER: S-EPMC6777606 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR.

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

European journal of human genetics : EJHG 20190611 10

The purpose of this study was to investigate influence of gene polymorphisms of APOB and APOE on risk of bleeding complications at therapeutic INR, during warfarin treatment in Korean patients with mechanical cardiac valves. The study included 142 patients from the EwhA-Severance Treatment Group (EAST) of Warfarin. A total of 12 SNPs was investigated. Five SNPs of APOB (c.13013G>A, c.1853C>T, c.1594C>T, c.293C>T, and c.7545C>T) and five SNPs of APOE (g.4798T>G, g.6406G>A, g.10413T>C, c.388T>C, a ...[more]

PMID: 31186542

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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:BackgroundWarfarin, a frequently prescribed oral anticoagulant, is well known for its narrow therapeutic index. Adherence to warfarin may help to achieve a stable international normalized ratio (INR), but little data are available regarding the impact of using a pillbox as a potential adherence aid device.ObjectiveTo evaluate the association between pillbox use and time in therapeutic range (TTR) < 60% and INR instability pattern.MethodsThis study was based on a prospective cohort of 1,069 new warfarin users who initiated warfarin between May 2010 and July 2013 within 17 hospitals in Quebec, Canada. Demographic, lifestyle, and clinical data were collected for 3 months to a year after warfarin initiation, and genetic factors were assessed. Patients usingh self-prepared and pharmacist-prepared pillboxes were compared with nonusers for the 3- to 12-month follow-up period. The primary outcome was a TTR < 60%, which represents a low percentage of time in the INR therapeutic range or an unstable patient. The secondary outcome was the INR instability pattern (unstable below range; unstable over range; unstable with erratic pattern; and stable) to better describe patient INR profiles. A multivariate generalized linear mixed model was used for the primary outcome, along with a multivariate multinomial linear mixed model for the secondary outcome.ResultsThe cohort included patients with a mean age of 70.4 ± 11.7 years; 61.8% of patients were men; 76.3% had atrial fibrillation as warfarin's primary indication; and 35.6% had a previous history of myocardial infarction or angina. Self-prepared and pharmacist-prepared pillbox use was not associated with TTR < 60% or a specific INR instability pattern. A sensitivity analysis showed that self-prepared pillbox users had a higher TTR than nonusers (3.55% ± 1.69%; P = 0.036). This effect was greater among patients aged < 70 years (5.48% ± 2.50%; P = 0.029) than among older patients (1.92% ± 2.31%; P =0.406).ConclusionsPillbox use was not associated with TTR < 60% or a specific INR instability pattern. The impact of self-prepared pillbox use was greater among younger patients, but results were not clinically significant. Future studies adjusting for concomitant drug use are needed to clarify these results.DisclosuresThis study was funded by Canadian Institutes of Health Research (CIHR) and the Centre for Excellence in Personalised Medicine. Both funding sources were not involved in the design, conduct, and reporting of this study. The data used for this study came from the Quebec Warfarin Cohort Study (QWCS), which was supported by the CIHR and the Centre for Excellence in Personalised Medicine. Dumas received a doctoral training award from the CIHR. Perreault and Dubé received a salary award from the Fonds Québécois de Recherche en Santé. Study concept and design were contributed by Talajic, Tardif, Dubé, and Perreault. Dumas, Rouleau-Mailloux, Bouchama, and Lahcene collected the data, which was interpreted by Dumas, Dubé, and Perreault. The manuscript was written and revised by Dumas, Dubé, and Perreault.

Dataset Information

APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR.

Publications

APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR.

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