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The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The logistic model to predict the recurrence used thromboxane A synthase 1 (<jats:italic>TXAS1<\/jats:italic>, rs41708) A\/A genotype and <jats:italic>ALOX12<\/jats:italic> promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, <jats:italic>COX2<\/jats:italic> (rs20417) C\/G and thromboxane A2 receptor (rs1131882) A\/A genotypes with the addition of <jats:italic>COX1<\/jats:italic> and <jats:italic>ALOX15<\/jats:italic> promoter methylations as variables. The linear PRU prediction model included G\/A and prostaglandin I receptor (rs4987262) G\/A genotypes, <jats:italic>COX2<\/jats:italic> and <jats:italic>TXAS1<\/jats:italic> promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A\/A, G\/A, and *3 (rs4986893) A\/A genotypes as variables. The linear models for predicting ARU (<jats:italic>r<\/jats:italic>\u2009=\u20090.291, R<jats:sup>2<\/jats:sup>\u2009=\u20090.033, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and PRU (<jats:italic>r<\/jats:italic>\u2009=\u20090.503, R<jats:sup>2<\/jats:sup>\u2009=\u20090.210, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>URL: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>; Unique identifier: NCT03823274.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-024-01936-1","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T08:03:05Z","timestamp":1718870585000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance"],"prefix":"10.1186","volume":"17","author":[{"given":"Jei","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byoung-Soo","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ick","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Hwan","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Guk","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Hyun","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Rin","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Goo","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeseon","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu Sun","family":"Yum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Yun","family":"Chae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do-Hyung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keunsoo","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeyeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"key":"1936_CR1","first-page":"e000576","volume":"3","author":"K Krishnan","year":"2023","unstructured":"Krishnan K, Nguyen T, Appleton JP, Law K, Caulfield M, Cabrera CP, Lenthall R, Hewson D, Engalnd T, McConachie N, et al. 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Int J Environ Res Public Health. 2023;20:912.","journal-title":"Int J Environ Res Public Health"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-024-01936-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-024-01936-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-024-01936-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T08:05:13Z","timestamp":1718870713000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-024-01936-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,20]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1936"],"URL":"https:\/\/doi.org\/10.1186\/s12920-024-01936-1","relation":{},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,20]]},"assertion":[{"value":"30 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study protocol for the present study was reviewed and approved by the Institutional Review Board (IRB) of the six hospitals participated in the study: Chungnam National University Hospital (IRB Approval No., CNUH-2018-12-033), Daejeon; Jeonbuk National University Hospital (CUH-2019-01-027), Jeonju; Dong-A University Hospital (DAUHIRB-19-048), Busan; Chungbuk National University Hospital (CBNUH-2019-01-015), Cheongju; Chosun University Hospital (CHOSUN-2019-02-006), Gwangju; and Eulji University Hospital (EMC-209-01-009-001), Daejeon, South Korea. The study protocol was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki after obtaining written informed consent from all patients before their enrolment into the trial.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"166"}}