AUTHOR=Jang Eun Jeong , Kim Jung Sun , Choi Seo A. , Yee Jeong , Song Tae-Jin , Park Junbeom , Gwak Hye Sun 

TITLE=Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1290785

DOI=10.3389/fphar.2023.1290785

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (<italic>RYR2</italic>) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between <italic>RYR2</italic> and bleeding risk to develop the risk scoring system in patients treated with DOACs.</p><p><bold>Methods:</bold> This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the <italic>RYR2</italic> 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.</p><p><bold>Results:</bold> 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) &lt; 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, <italic>RYR2</italic> 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.</p><p><bold>Conclusion:</bold> This study revealed an association between <italic>RYR2</italic> and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.</p>