{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:08:48Z","timestamp":1789013328444,"version":"build-2803163510"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Thoracic aortic aneurysm (TAA) is a significant public health concern. We aimed to identify drug targets and understand the pathogenic mechanisms of TAA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We employed 4907 circulating proteins as exposure data from a large\u2010scale protein quantitative trait loci study involving 35\u2009559 Icelanders. We used findings from the FinnGen study as the outcome data. We conducted bidirectional Mendelian randomization analysis and colocalization analysis to pinpoint potential therapeutic targets for TAA and validated the results in the UK Biobank database. We validated findings with plasma transcriptomics and single\u2010cell sequencing to uncover the pathological mechanisms of TAA. Western blots and immunofluorescence staining examined potential drug targets in aortic tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Mendelian randomization results suggest that LTBP4 (latent transforming growth factor \u03b2\u2013binding protein 4) is significantly associated with the risk of TAA. Plasma transcriptomics showed significantly increased LTBP4 expression in patients with TAA (log fold change=0.69, adjusted\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =7.04\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), with an area under the curve of 0.76. The single\u2010cell sequencing analysis highlighted the predominant expression of LTBP4 in fibroblasts and the central role of LTBP4 in the functional regulation of the transforming growth factor \u03b2 pathway. In\u00a0vitro experiments demonstrate that the expression of LTBP4 protein is significantly increased in TAA tissue. Immunofluorescence staining indicates that LTBP4 is primarily localized in the extracellular matrix of the medial layer of the aorta.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study presents an innovative integration of Mendelian randomization with multi\u2010omics and in\u00a0vitro experiments, identifying LTBP4 as a candidate therapeutic target for TAA. It also underscores the role of LTBP4 in regulating the transforming growth factor \u03b2 signaling pathway within the pathogenic mechanism of TAA, particularly within fibroblast cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.047276","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T10:17:43Z","timestamp":1784974663000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Omics Analysis for Pathogenesis and Candidate Therapeutic Target in Thoracic Aortic Aneurysms"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1992-6757","authenticated-orcid":false,"given":"Haoyu","family":"Gao","sequence":"first","affiliation":[{"name":"Sichuan University","place":["Chengdu, China"]},{"name":"Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Xie","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Li","sequence":"additional","affiliation":[{"name":"Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqiang","family":"Guo","sequence":"additional","affiliation":[{"name":"Sichuan University","place":["Chengdu, China"]},{"name":"Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1789-5006","authenticated-orcid":false,"given":"Jun","family":"Shi","sequence":"additional","affiliation":[{"name":"Sichuan University","place":["Chengdu, China"]},{"name":"Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001106"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.2012.0227"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05512-x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104199"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k601"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104494"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34408"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3538"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046528"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100498"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2008.06.016"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.11.014"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90069-q"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.47.29891"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2022.01.005"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.05.005"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.09.013"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.322494"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8050649"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2017.43"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32219-x"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.122.317953"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.121.317007"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.026005"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jjcc.2016.05.007"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2009.09.073"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.125.047276","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:41:25Z","timestamp":1789011685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.125.047276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":31,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,8,4]]}},"alternative-id":["10.1161\/JAHA.125.047276"],"URL":"https:\/\/doi.org\/10.1161\/jaha.125.047276","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"assertion":[{"value":"2025-10-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e047276"}}