{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T17:55:48Z","timestamp":1781546148031,"version":"3.54.5"},"reference-count":32,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":165,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"XZHMU-QL Joint Research Fund","award":["QL-YB082"],"award-info":[{"award-number":["QL-YB082"]}]},{"name":"Advanced Program of the Affiliated Hospital of Xuzhou Medical University","award":["PYJH2025308"],"award-info":[{"award-number":["PYJH2025308"]}]},{"name":"Construction Project of High Level Hospital of Jiangsu Province","award":["LCZX202412"],"award-info":[{"award-number":["LCZX202412"]}]},{"name":"Medical Science and Technology Innovation Project of Xuzhou Municipal Health Commission","award":["XWKYHT20230067"],"award-info":[{"award-number":["XWKYHT20230067"]}]},{"name":"Project of the Affiliated Hospital of Xuzhou Medical University","award":["2022ZL20"],"award-info":[{"award-number":["2022ZL20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Emerging evidence implicates peripheral metabolic disturbances in the pathogenesis of cerebrovascular diseases. However, the specific molecular conduits linking angina pectoris (AP) to ischemic stroke (IS) remain elusive. To address this, we evaluated the causal effect of AP on IS subtypes utilizing Bayesian-weighted Mendelian randomization (BWMR) based on large-scale GWAS meta-data (n\u2009=\u2009628\u00a0000). Cross-tissue transcriptomic analyses, coupled with the Boruta feature selection algorithm, were employed to screen for candidate mediators, with subsequent validation of genetic causality and therapeutic viability via standard Mendelian randomization (MR), colocalization analysis, and molecular docking. Furthermore, their involvement in cellular immunity was characterized using CIBERSORT and single-cell ribonucleic acid-seq (scRNA-seq). BWMR established a robust causal relationship from stable AP to IS (OR\u2009=\u20091.13, P\u2009=\u2009.004). Multi-omics integration identified 18 hub macromolecules, prioritizing HMGCR, TLR4, and MMP9 as the primary candidate mediators enriched in lipid metabolism and inflammatory pathways. MR corroborated the genetic relevance of these loci to IS risk, while molecular docking confirmed their structural druggability. A multilayer perceptron classifier (MLPC) utilizing these targets demonstrated high predictive accuracy for IS (AUC\u2009=\u20090.82\u20130.90). Crucially, scRNA-seq revealed that TLR4 and MMP9 expression in peripheral immune cells (CD8+ T cells and neutrophils) may drive a metabolic-inflammatory cascade, functioning as vital conduits for peripheral-to-brain signal transduction. In conclusion, this multi-omics framework identifies HMGCR, TLR4, and MMP9 as genetically supported mediators bridging AP and IS, elucidating peripheral\u2013cerebral crosstalk and highlighting actionable targets for clinical risk stratification and pharmacological repurposing.<\/jats:p>","DOI":"10.1093\/bfgp\/elag004","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:46:17Z","timestamp":1780659977000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetically supported mediators linking peripheral metabolism to cerebral ischemia: a multi-omics characterization of HMGCR, TLR4, and MMP9 in angina pectoris and stroke"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2891-9863","authenticated-orcid":false,"given":"Ying","family":"Li","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University , 99# Huai-hai West Road, Xuzhou, Jiangsu, 221004 ,","place":["China"]},{"name":"Precision Medicine Center of the Affiliated Hospital of Xuzhou Medical University , 99# Huaihai West Road, Quanshan District, Xuzhou, Jiangsu, 221002 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5175-9833","authenticated-orcid":false,"given":"Haozhou","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , 197# Ruijin 2nd Road, Huangpu District, Shanghai 200025 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Xuzhou Cancer Hospital , 131 Huancheng Road, Gulou District, Xuzhou, Jiangsu, 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenggang","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Xuzhou Medical University , 209 Tongshan Road, Xuzhou, Jiangsu, 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-0770","authenticated-orcid":false,"given":"Qian","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University , 99# Huai-hai West Road, Xuzhou, Jiangsu, 221004 ,","place":["China"]},{"name":"Precision Medicine Center of the Affiliated Hospital of Xuzhou Medical University , 99# Huaihai West Road, Quanshan District, Xuzhou, Jiangsu, 221002 ,","place":["China"]},{"name":"School of Medical Technology, Xuzhou Medical University , 209 Tongshan Road, Xuzhou, Jiangsu, 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"2026061513280470800_ref1","doi-asserted-by":"publisher","first-page":"e137","DOI":"10.1212\/WNL.0000000000207387","article-title":"Global burden, risk factor analysis, and prediction study of ischemic stroke, 1990\u20132030","volume":"101","author":"Fan","year":"2023","journal-title":"Neurology"},{"key":"2026061513280470800_ref2","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s40120-021-00310-y","article-title":"Migraine and ischemic stroke: a Mendelian randomization study","volume":"11","author":"Shu","year":"2022","journal-title":"Neurol Ther"},{"key":"2026061513280470800_ref3","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1161\/STROKEAHA.120.028992","article-title":"Risk and secondary prevention of stroke recurrence: a population-base cohort study","volume":"51","author":"Flach","year":"2020","journal-title":"Stroke"},{"key":"2026061513280470800_ref4","doi-asserted-by":"publisher","first-page":"200249","DOI":"10.1016\/j.ijcrp.2024.200249","article-title":"Risk scores for prediction of paroxysmal atrial fibrillation after acute ischemic stroke or transient ischemic attack: a systematic review and meta-analysis","volume":"21","author":"Kazemian","year":"2024","journal-title":"Int J Cardiol Cardiovasc Risk Prev"},{"key":"2026061513280470800_ref5","doi-asserted-by":"publisher","first-page":"E11349","DOI":"10.1073\/pnas.1810568115","article-title":"Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics","volume":"115","author":"Krause","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026061513280470800_ref6","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s44161-024-00475-3","article-title":"Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease","volume":"3","author":"Malik","year":"2024","journal-title":"Nat Cardiovasc Res"},{"key":"2026061513280470800_ref7","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1136\/heartjnl-2023-322345","article-title":"Prevalence of angina pectoris and association with coronary atherosclerosis in a general population","volume":"109","author":"Wel\u00e9n Schef","year":"2023","journal-title":"Heart Br Card Soc"},{"key":"2026061513280470800_ref8","doi-asserted-by":"publisher","first-page":"e004080","DOI":"10.1161\/JAHA.116.004080","article-title":"Angina and future cardiovascular events in stable patients with coronary artery disease: insights from the reduction of atherothrombosis for continued health (REACH) registry","volume":"5","author":"Eisen","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"2026061513280470800_ref9","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1161\/hs0102.101630","article-title":"Severity of angina pectoris and risk of ischemic stroke","volume":"33","author":"Tanne","year":"2002","journal-title":"Stroke"},{"key":"2026061513280470800_ref10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"2026061513280470800_ref11","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1093\/bioinformatics\/btz749","article-title":"Bayesian weighted mendelian randomization for causal inference based on summary statistics","volume":"36","author":"Zhao","year":"2020","journal-title":"Bioinformatics"},{"key":"2026061513280470800_ref12","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41588-021-00931-x","article-title":"A cross-population atlas of genetic associations for 220 human phenotypes","volume":"53","author":"Sakaue","year":"2021","journal-title":"Nat Genet"},{"key":"2026061513280470800_ref13","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41588-018-0058-3","article-title":"Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes","volume":"50","author":"Malik","year":"2018","journal-title":"Nat Genet"},{"key":"2026061513280470800_ref14","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1177\/0962280215597579","article-title":"A review of instrumental variable estimators for mendelian randomization","volume":"26","author":"Burgess","year":"2017","journal-title":"Stat Methods Med Res"},{"key":"2026061513280470800_ref15","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in mendelian randomization: a blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur J Epidemiol"},{"key":"2026061513280470800_ref16","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jclinepi.2014.09.005","article-title":"Cochran\u2019s Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy","volume":"68","author":"Cohen","year":"2015","journal-title":"J Clin Epidemiol"},{"key":"2026061513280470800_ref17","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1186\/s12874-022-01619-4","article-title":"Bayesian mendelian randomization with study heterogeneity and data partitioning for large studies","volume":"22","author":"Zou","year":"2022","journal-title":"BMC Med Res Methodol"},{"key":"2026061513280470800_ref18","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"2026061513280470800_ref19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jad.2025.01.140","article-title":"Genome-wide mendelian randomization mapping the influence of plasma proteome on major depressive disorder","volume":"376","author":"Li","year":"2025","journal-title":"J Affect Disord"},{"key":"2026061513280470800_ref20","doi-asserted-by":"publisher","first-page":"3069","DOI":"10.1093\/bioinformatics\/btv313","article-title":"DSigDB: drug signatures database for gene set analysis","volume":"31","author":"Yoo","year":"2015","journal-title":"Bioinformatics"},{"key":"2026061513280470800_ref21","doi-asserted-by":"publisher","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2026061513280470800_ref22","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1161\/CIRCRESAHA.114.302721","article-title":"Mechanisms of plaque formation and rupture","volume":"114","author":"Bentzon","year":"2014","journal-title":"Circ Res"},{"key":"2026061513280470800_ref23","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1161\/STROKEAHA.115.012004","article-title":"Atrial fibrillation and mechanisms of stroke: time for a new model","volume":"47","author":"Kamel","year":"2016","journal-title":"Stroke"},{"key":"2026061513280470800_ref24","doi-asserted-by":"publisher","first-page":"302","DOI":"10.5853\/jos.2017.02922","article-title":"Cerebral small vessel disease: a review focusing on pathophysiology, biomarkers, and machine learning strategies","volume":"20","author":"Cuadrado-Godia","year":"2018","journal-title":"J Stroke"},{"key":"2026061513280470800_ref25","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1111\/j.1742-7843.2010.00548.x","article-title":"Puerarin inhibits C-reactive protein expression via suppression of nuclear factor kappaB activation in lipopolysaccharide-induced peripheral blood mononuclear cells of patients with stable angina pectoris","volume":"107","author":"Yang","year":"2010","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"2026061513280470800_ref26","doi-asserted-by":"publisher","first-page":"155271","DOI":"10.1016\/j.phymed.2023.155271","article-title":"Chlorogenic acid regulates the expression of NPC1L1 and HMGCR through PXR and SREBP2 signaling pathways and their interactions with HSP90 to maintain cholesterol homeostasis","volume":"123","author":"Meng","year":"2024","journal-title":"Phytomedicine Int J Phytother Phytopharm"},{"key":"2026061513280470800_ref27","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1186\/s12872-024-03957-1","article-title":"LY86 facilitates ox-LDL-induced lipid accumulation in macrophages by upregulating SREBP2\/HMGCR expression","volume":"24","author":"Jiang","year":"2024","journal-title":"BMC Cardiovasc Disord"},{"key":"2026061513280470800_ref28","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1111\/ene.15342","article-title":"Predictive values of baseline matrix metalloproteinase 9 levels in peripheral blood on 3-month outcomes of high-risk patients with minor stroke or transient ischemic attack","volume":"29","author":"Zhang","year":"2022","journal-title":"Eur J Neurol"},{"key":"2026061513280470800_ref29","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic induction of trained immunity through the mevalonate pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"2026061513280470800_ref30","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.atherosclerosis.2011.12.030","article-title":"Differential expression of toll-like receptor 4 and human monocyte subsets in acute myocardial infarction","volume":"221","author":"Kashiwagi","year":"2012","journal-title":"Atherosclerosis"},{"key":"2026061513280470800_ref31","doi-asserted-by":"publisher","first-page":"757872","DOI":"10.3389\/fimmu.2021.757872","article-title":"Role of TLR4 in neutrophil dynamics and functions: contribution to stroke pathophysiology","volume":"12","author":"Dur\u00e1n-Laforet","year":"2021","journal-title":"Front Immunol"},{"key":"2026061513280470800_ref32","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1096\/fj.03-0110com","article-title":"Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway","volume":"17","author":"Baumann","year":"2003","journal-title":"FASEB J Off Publ Fed Am Soc Exp Biol"}],"container-title":["Briefings in Functional Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bfg\/article-pdf\/doi\/10.1093\/bfgp\/elag004\/68529603\/elag004.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bfg\/article-pdf\/doi\/10.1093\/bfgp\/elag004\/68529603\/elag004.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T17:28:08Z","timestamp":1781544488000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bfg\/article\/doi\/10.1093\/bfgp\/elag004\/8708285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":32,"URL":"https:\/\/doi.org\/10.1093\/bfgp\/elag004","relation":{},"ISSN":["2041-2649","2041-2657"],"issn-type":[{"value":"2041-2649","type":"print"},{"value":"2041-2657","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"elag004"}}