{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:09:21Z","timestamp":1778605761947,"version":"3.51.4"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Patients with type 2 diabetes mellitus (T2DM) have a two- to fourfold higher risk of myocardial infarction (MI), yet genetic determinants of this excess risk remain incompletely defined. The JCAD (junctional cadherin 5 associated; formerly KIAA1462) locus has been implicated in coronary artery disease through genome-wide association studies, but data in diabetic populations are scarce. Objectives: To assess whether the rs3739998 polymorphism of JCAD is associated with MI in Slovenian subjects with T2DM and to explore its relationship with coronary disease burden and coronary artery calcium (CAC). Methods: We performed a retrospective cross-sectional association study of 1471 Slovenian subjects with T2DM: 387 with prior MI and 1084 without clinical evidence of coronary artery disease. Genotyping for JCAD rs3739998 was performed using a fluorescence-based competitive allele-specific PCR (KASPar). A coronary computed tomographic angiography (CCTA) substudy (n = 146) evaluated the number of diseased coronary arteries, stenosis severity, and CAC score. Results: The GG genotype was more frequently observed in MI cases compared to controls in unadjusted analysis (OR 1.37; p = 0.05) but association was lost with adjustment for confounders (GG vs. CC, aOR 1.63, p = 0.09). The G allele was also more prevalent among cases (OR 1.18; p = 0.05, unadjusted analysis). In the CCTA substudy, no significant associations were observed between rs3739998 and the number of diseased vessels, stenosis grade, or CAC. Conclusions: In a Slovenian T2DM cohort, the JCAD rs3739998 G allele and GG genotype showed a nominal association with prior MI that did not persist after multivariable adjustment. There was no clear relationship with anatomic disease burden or CAC, underscoring the need for replication in larger cohorts and functional studies to clarify the mechanism and clinical utility.<\/jats:p>","DOI":"10.3390\/genes16111378","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:44:55Z","timestamp":1762865095000},"page":"1378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The G Allele and GG Genotype of the Junctional Cadherin 5 Associated (JCAD) Is a Biomarker Predicting Myocardial Infarction in Slovenian Subjects with Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-262X","authenticated-orcid":false,"given":"Miha","family":"Tibaut","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, General Hospital Raki\u010dan, Ulica dr. Vrbnjaka 6, 9000 Murska Sobota, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danijel","family":"Petrovi\u010d","sequence":"additional","affiliation":[{"name":"Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1105 Ljubljana, Slovenia"},{"name":"International Centre for Cardiovascular Diseases MC Medicor d.d., 6310 Izola, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","unstructured":"Organisation Mondiale de la Sant\u00e9 (2014). Global Status Report on Noncommunicable Diseases 2014: Attaining the Nine Global Noncommunicable Diseases Targets; A Shared Responsibility, World Health Organization."},{"key":"ref_2","unstructured":"National Institute of Public Health Slovenia (2022, November 14). Ekonomsko Breme Sladkorne Bolezni v Sloveniji 2012, Available online: http:\/\/www.nijz.si\/ekonomsko-brhttp:\/\/www.mz.gov.si\/fileadmin\/mz.gov.si\/pageuploads\/javno_zdravje_2015\/breme_sladkorn%20e.docx."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11010-009-0148-8","article-title":"Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart","volume":"331","author":"Hussain","year":"2009","journal-title":"Mol. Cell. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The Pathobiology of Diabetic Complications: A Unifying Mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2174\/1871525714666160407143416","article-title":"Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus","volume":"14","author":"Tibaut","year":"2016","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jacc.2016.11.056","article-title":"Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated with Coronary Artery Disease","volume":"69","author":"Webb","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1093\/eurheartj\/ehz303","article-title":"The novel coronary artery disease risk gene JCAD\/KIAA1462 promotes endothelial dysfunction and atherosclerosis","volume":"40","author":"Xu","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1161\/ATVBAHA.118.310976","article-title":"JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells","volume":"38","author":"Jones","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1093\/eurheartj\/ehq405","article-title":"Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23","volume":"32","author":"Erdmann","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Coronary Artery Disease (C4D) Genetics Consortium (2011). A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat. Genet., 43, 339\u2013344.","DOI":"10.1038\/ng.782"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40246-018-0189-8","article-title":"The association of functional polymorphisms in genes expressed in endothelial cells and smooth muscle cells with the myocardial infarction","volume":"13","author":"Li","year":"2019","journal-title":"Hum. Genom."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2021). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes\u20142021. Diabetes Care, 44, S15\u2013S33.","DOI":"10.2337\/dc21-S002"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1093\/eurheartj\/ehy462","article-title":"Fourth universal definition of myocardial infarction (2018)","volume":"40","author":"Thygesen","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1016\/S0140-6736(05)67663-5","article-title":"Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: A case-control study","volume":"366","author":"Yusuf","year":"2005","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bbrc.2011.08.073","article-title":"A coronary artery disease-associated gene product, JCAD\/KIAA1462, is a novel component of endothelial cell-cell junctions","volume":"413","author":"Akashi","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e05121","DOI":"10.1016\/j.heliyon.2020.e05121","article-title":"JCAD expression and localization in human blood endothelial cells","volume":"6","author":"Shigeoka","year":"2020","journal-title":"Heliyon"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1093\/cvr\/cvz263","article-title":"A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction","volume":"116","author":"Douglas","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1161\/ATVBAHA.117.309721","article-title":"Targeted Disruption of JCAD (Junctional Protein Associated with Coronary Artery Disease)\/KIAA1462, a Coronary Artery Disease-Associated Gene Product, Inhibits Angiogenic Processes In Vitro and In Vivo","volume":"37","author":"Hara","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1164\/rccm.201605-0997OC","article-title":"Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution","volume":"195","author":"Boueiz","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Murdock, D.G., Bradford, Y., Schnetz-Boutaud, N., Mayo, P., Allen, M.J., D\u2019aOust, L.N., Liang, X., Mitchell, S.L., Zuchner, S., and Small, G.W. (2013). KIAA1462, a coronary artery disease associated gene, is a candidate gene for late onset Alzheimer disease in APOE carriers. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082194"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.ygyno.2013.06.007","article-title":"Whole exome sequence analysis of serous borderline tumors of the ovary","volume":"130","author":"Boyd","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5287","DOI":"10.1158\/0008-5472.CAN-17-0229","article-title":"JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity","volume":"77","author":"Ye","year":"2017","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"731","DOI":"10.2174\/1566524019666190828151540","article-title":"Identification of Phosphorylation Associated SNPs for Blood Pressure, Coronary Artery Disease and Stroke from Genome-wide Association Studies","volume":"19","author":"Wang","year":"2019","journal-title":"Curr. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, R., Zhang, H., Tang, F., Duan, C., Liu, D., Wu, N., Zhang, Y., Wang, L., and Mo, X. (2022). Coronary artery disease risk factors affected by RNA modification-related genetic variants. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.985121"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1134\/S0026893320020041","article-title":"Genetic Predisposition to Early Myocardial Infarction","volume":"54","author":"Goncharova","year":"2020","journal-title":"Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9738567","DOI":"10.1155\/2020\/9738567","article-title":"Association Study of Coronary Artery Disease-Associated Genome-Wide Significant SNPs with Coronary Stenosis in Pakistani Population","volume":"2020","author":"Cheema","year":"2020","journal-title":"Dis. Markers"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Arellano, M.E., Solares-Tlapechco, J., Costa-Urrutia, P., C\u00e1rdenas-Hern\u00e1ndez, H., Vallejo-G\u00f3mez, M., Granados, J., and Salas-Padilla, S. (2020). Association of the PSRC1 rs599839 Variant with Coronary Artery Disease in a Mexican Population. Medicina, 56.","DOI":"10.3390\/medicina56090427"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1093\/eurheartj\/ehac641","article-title":"JCAD promotes arterial thrombosis through PI3K\/Akt modulation: A translational study","volume":"44","author":"Liberale","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.2174\/1871525714666161216100553","article-title":"Pathophysiology of Myocardial Infarction and Acute Management Strategies","volume":"14","author":"Tibaut","year":"2017","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/11\/1378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:20:37Z","timestamp":1778602837000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/11\/1378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["genes16111378"],"URL":"https:\/\/doi.org\/10.3390\/genes16111378","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]}}}