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However, variability in drug response poses risks of hemorrhagic or thromboembolic events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Although genetic influences on DOACs safety are increasingly recognized, robust evidence directly linking specific polymorphisms to bleeding risk remains limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Multi-center observational case\u2013control study including exome-wide association analysis of 196 non-valvular AF patients treated with rivaroxaban or apixaban, comprising 97 with bleeding complications and 99 without.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DOAC plasma concentrations, urinary 6-\u03b2-hydroxycortisol and cortisol levels were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single-nucleotide variant (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Polygenic risk scores (PRSs) were calculated to evaluate cumulative genetic effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      No SNVs reached Bonferroni-corrected significance under any model. PRSs showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln\u2005C\n                      <jats:sub>ss min<\/jats:sub>\n                      \/D\u2009+\u20091 index increased with PRS, age, and 6-\u03b2-hydroxycortisol\/cortisol ratio, but decreased with higher 6-\u03b2-hydroxycortisol and coronary heart disease presence. No statistically significant differences were found for the PharmGKB Level 3 variants rs1045642 (rivaroxaban) and rs2231142 (apixaban). Trends toward statistical significance were observed for the rs2472304-G variant in rivaroxaban users, rs6977165-C in apixaban users, and for the\n                      <jats:italic toggle=\"yes\">CYP3A4*1\/*36<\/jats:italic>\n                      diplotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Residual equilibrium concentration of DOACs, including dose-adjusted, did not independently predict bleeding risk in non-valvular AF patients. Variants rs2472304 and rs6977165 may warrant further investigation as potential contributors to bleeding risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/00368504251398881","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T15:21:13Z","timestamp":1764343273000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Exome-wide association study of bleeding events in patients receiving direct oral anticoagulants"],"prefix":"10.1177","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry A","family":"Sychev","sequence":"first","affiliation":[{"name":"Russian Medical Academy of Continuous Professional Education"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-9222","authenticated-orcid":false,"given":"Anastasiia 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