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Published on: April 1, 2019
Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants
Ha-Young Yoon1, Tae-Jin Song2, Jeong Yee1
1College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea.
Insights
Genetic variations in APOB and APOE influence bleeding risk in patients taking direct oral anticoagulants (DOACs). Incorporating these genetic factors improves bleeding risk prediction models for personalized DOAC therapy.
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Clinical Genetics
Background:
- Direct oral anticoagulants (DOACs) are widely used for thromboprophylaxis.
- Bleeding complications remain a significant concern in patients treated with DOACs.
- Individual variability in DOAC response necessitates personalized treatment strategies.
Purpose of the Study:
- To investigate the association between apolipoprotein B (APOB) and apolipoprotein E (APOE) gene polymorphisms and bleeding complications in patients on DOACs.
- To evaluate the impact of incorporating genetic factors into risk prediction models for DOAC-associated bleeding.
Main Methods:
- Genotyping of 16 single nucleotide polymorphisms (SNPs) in ABCB1, CYP3A5, APOB, and APOE genes in 468 patients.
- Multivariable logistic regression analysis to construct risk scoring systems, comparing models with and without genetic factors.
- Analysis of area under the receiver operating characteristic curve (AUROC) to assess model performance.
Main Results:
- Rivaroxaban use and anemia were independently associated with increased bleeding risk.
- Specific variants in ABCB1 (rs3842) and APOB (rs13306198) were linked to a higher risk of bleeding.
- The inclusion of genetic factors in the risk model significantly improved the AUROC from 0.65 to 0.72.
Conclusions:
- APOB and APOE gene polymorphisms, along with demographic factors, can enhance the prediction of bleeding risk in patients receiving DOACs.
- These findings support the development of individualized treatment strategies for DOAC therapy.
- Improved bleeding risk prediction can aid clinicians in optimizing patient management and reducing adverse events.
Abstract:
Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56-0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65-0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.
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