Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants
Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1290785/full |
| _version_ | 1797614213504434176 |
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| author | Eun Jeong Jang Jung Sun Kim Seo A. Choi Jeong Yee Tae-Jin Song Junbeom Park Hye Sun Gwak |
| author_facet | Eun Jeong Jang Jung Sun Kim Seo A. Choi Jeong Yee Tae-Jin Song Junbeom Park Hye Sun Gwak |
| author_sort | Eun Jeong Jang |
| collection | DOAJ |
| description | Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs.Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system.Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1–2, 3–4, 5–6, 7–8, and 9–10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively.Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients. |
| first_indexed | 2024-03-11T07:06:36Z |
| format | Article |
| id | doaj.art-76ff7b374cf24eb4a8084cd76d517590 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-11T07:06:36Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-76ff7b374cf24eb4a8084cd76d5175902023-11-17T08:55:47ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-11-011410.3389/fphar.2023.12907851290785Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulantsEun Jeong Jang0Jung Sun Kim1Seo A. Choi2Jeong Yee3Tae-Jin Song4Junbeom Park5Hye Sun Gwak6College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaDepartment of Neurology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of KoreaDivision of Cardiology, Department of Internal Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaIntroduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs.Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system.Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1–2, 3–4, 5–6, 7–8, and 9–10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively.Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.https://www.frontiersin.org/articles/10.3389/fphar.2023.1290785/fulldirect oral anticoagulantsbleedingryanodine receptorspharmacogenomicsgene polymorphism |
| spellingShingle | Eun Jeong Jang Jung Sun Kim Seo A. Choi Jeong Yee Tae-Jin Song Junbeom Park Hye Sun Gwak Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants Frontiers in Pharmacology direct oral anticoagulants bleeding ryanodine receptors pharmacogenomics gene polymorphism |
| title | Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| title_full | Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| title_fullStr | Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| title_full_unstemmed | Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| title_short | Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| title_sort | construction of a risk scoring system using clinical factors and ryr2 polymorphisms for bleeding complications in patients on direct oral anticoagulants |
| topic | direct oral anticoagulants bleeding ryanodine receptors pharmacogenomics gene polymorphism |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1290785/full |
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