{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:29:01Z","timestamp":1793413741367,"version":"4.5.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["01-003-2022-0417 2022"],"award-info":[{"award-number":["01-003-2022-0417 2022"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EU HORIZON MIRACLE","award":["101115381"],"award-info":[{"award-number":["101115381"]}]},{"name":"VAR","award":["TKI-2003"],"award-info":[{"award-number":["TKI-2003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The aetiology of coronary artery disease (CAD) appears different for men and women, yet insights into underlying sex-specific biological mechanisms are limited. We integrated genomic and proteomic analyses to investigate sex-specific associations of the plasma proteome with CAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>In 40 829 UK Biobank participants (free-of-CAD, baseline 365 days thereafter; 55% women; mean age 56.9 \u00b1 8.1 years), we examined associations between 2922 plasma proteins and incident CAD over a median follow-up of 13.7 years (IQR 13.1\u201314.4) using multivariable-adjusted Cox proportional hazards models. Sex-specific analyses identified 440 female exclusive and 32 male exclusive proteins associated with incident CAD (FDR-corrected P &amp;lt; 0.05), revealing distinct pathway enrichments, including innate immune response in women and angiogenesis in men. Causality was assessed through combined and sex-stratified two-sample Mendelian randomization (MR) using inverse-variance-weighted analyses with genome-wide association summary statistics from 422 108 men (61 969 cases) and 521 695 women (27 128 cases) (UK Biobank, FinnGen freeze 9). Integration of direct sex-protein interaction analyses with sex-combined MR identified 59 proteins with evidence for sex-specific causal effects. Four proteins demonstrated concordant directionality in sex-stratified MR analyses (n = 943 803) and multivariable regression models, namely CDKN2D, MYH9, and SKAP2 (women) and CTSH (men). To assess translational relevance, prioritized targets were further evaluated in secondary major adverse cardiovascular events among carotid endarterectomy patients (MACE; Athero-Express) and acute myocardial infarction (AMI; MISSION!) using plasma proteomics and ELISA. After further top-target identification in the context of MACE and AMI, clinical drug candidates were identified through a machine learning framework, including CTSH (men) and TNFRSF4 (both sexes).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We identified sex-specific associations of proteins and biological pathways with incident CAD. Whereas the majority of proteins had consistent associations in both men and women, our findings suggest a degree of sex-specific pathogenesis with evidence for potential causality, opening new alleys for tailored prevention strategies and clinical cardiovascular risk management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag186","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:13:13Z","timestamp":1788423193000},"source":"Crossref","is-referenced-by-count":1,"title":["Sex-specific associations of the plasma proteome with incident coronary artery disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3463-1217","authenticated-orcid":false,"given":"Vincent Q","family":"Sier","sequence":"first","affiliation":[{"name":"Department of Surgery, Leiden University Medical Center , Albinusdreef 2, 2333ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3484-3999","authenticated-orcid":false,"given":"Kristina","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, 3508, GA, Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erna H A B","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Surgery, Leiden University Medical Center , Albinusdreef 2, 2333ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter P M","family":"van der Loo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2172-7394","authenticated-orcid":false,"given":"Ko","family":"Willems van Dijk","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]},{"name":"Department of Human Genetics, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]},{"name":"Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-7748","authenticated-orcid":false,"given":"Diana","family":"van Heemst","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelmina H","family":"Bax","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-5760","authenticated-orcid":false,"given":"Paul H A","family":"Quax","sequence":"additional","affiliation":[{"name":"Department of Surgery, Leiden University Medical Center , Albinusdreef 2, 2333ZA Leiden ,","place":["The Netherlands"]},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5345-1022","authenticated-orcid":false,"given":"Gerard","family":"Pasterkamp","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, 3508, GA, Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5298-4852","authenticated-orcid":false,"given":"Michal","family":"Mokry","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, 3508, GA, Utrecht ,","place":["The Netherlands"]},{"name":"Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, 3508, GA, Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3246-8359","authenticated-orcid":false,"given":"J Wouter","family":"Jukema","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]},{"name":"Netherlands Heart Institute , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-809X","authenticated-orcid":false,"given":"Raymond","family":"Noordam","sequence":"additional","affiliation":[{"name":"Health Campus the Hague\/Public Health and Primary Care, Leiden University Medical Center , The Hague\/Leiden ,","place":["The Netherlands"]},{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden ,","place":["The 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