{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:12:25Z","timestamp":1790107945389,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2023 Open Foundation of Key Laboratory of Forensic Pathology, Ministry of Public Security, P. R. China","award":["GAFYBL202302"],"award-info":[{"award-number":["GAFYBL202302"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sudden cardiac death (SCD) is a major cause of mortality among patients with coronary artery disease (CAD). This study aimed to identify risk factors for CAD-related SCD (SCDCAD) through autopsy data and genetic screening with a particular emphasis on rare variants (minor allele frequency &lt; 0.01). We included 241 SCDCAD cases (mean age 54.6 \u00b1 12.8 years, 74.7% male) verified by medico-legal examination and 241 silent CAD controls (mean age 53.6 \u00b1 15.2 years, 25.3% female) who died from severe craniocerebral trauma. Information about death characteristics was obtained from questionnaires, police reports and autopsy data. Whole-exome sequencing was performed on myocardial tissue samples. Polygenic risk score (PRS) from a previously validated model was applied and rare variant pathogenicity was predicted using in silico tools. SCDCAD victims predominantly died at night and showed higher mortality rates during summer and winter months, with more complex coronary disease. Nocturnal time (adjusted odds ratio [AOR] = 3.53, 95% CI: 2.37\u20135.25, p &lt; 0.001), winter (AOR = 2.06, 95% CI: 1.33\u20133.20, p = 0.001), multiple vessel occlusion (AOR = 1.79, 95% CI: 1.16\u20132.77, p = 0.009), right coronary artery stenosis (AOR = 2.38, 95% CI: 1.54\u20133.68, p &lt; 0.001) and unstable plaque (AOR = 2.17, 95% CI: 1.46\u20133.23, p &lt; 0.001) were identified as risk factors of SCDCAD. The PRS score was associated with a 60% increased risk of SCDCAD (OR = 1.632 per SD, 95%CI: 1.631\u20131.633, p &lt; 0.001). Genetic analysis identified MUC19 and CGN as being associated with SCDCAD. We identified both hereditary and acquired risk factors that may contribute to cardiac dysfunction and precipitate SCD in CAD patients, thereby facilitating the prevention and early recognition of high-risk individuals.<\/jats:p>","DOI":"10.3390\/ijms26083470","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T11:05:02Z","timestamp":1744110302000},"page":"3470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Risk Factors and Genetic Insights into Coronary Artery Disease-Related Sudden Cardiac Death: A Molecular Analysis of Forensic Investigation"],"prefix":"10.3390","volume":"26","author":[{"given":"Xiangwang","family":"He","sequence":"first","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-603X","authenticated-orcid":false,"given":"Libing","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, West China School of Basic Medical Sciences & Forensic Science, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.hrthm.2021.05.005","article-title":"Nationwide burden of sudden cardiac death: A study of 54,028 deaths in Denmark","volume":"18","author":"Lynge","year":"2021","journal-title":"Heart Rhythm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.31083\/j.rcm.2021.01.207","article-title":"Sudden cardiac death: Epidemiology, pathogenesis and management","volume":"22","author":"Kumar","year":"2021","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13693","DOI":"10.1111\/eci.13693","article-title":"The role of metabolic syndrome in sudden cardiac death risk: Recent evidence and future directions","volume":"52","author":"Tirandi","year":"2022","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"807","DOI":"10.31083\/j.rcm2203087","article-title":"Sudden cardiac death in patients with myocardial infarction: 1.5 primary prevention","volume":"22","author":"Feng","year":"2021","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s12955-020-01312-4","article-title":"Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain","volume":"18","author":"Rieckmann","year":"2020","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/MOL.0000000000000277","article-title":"What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?","volume":"27","author":"Jeff","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41576-024-00709-x","article-title":"Genetic variation across and within individuals","volume":"25","author":"Yu","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/s41588-024-01791-x","article-title":"Exome sequence analysis identifies rare coding variants associated with a machine learning-based marker for coronary artery disease","volume":"56","author":"Petrazzini","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e036499","DOI":"10.1161\/JAHA.124.036499","article-title":"Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants","volume":"14","author":"Iyer","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1001\/jamacardio.2021.1573","article-title":"Genetic Variants Associated with Unexplained Sudden Cardiac Death in Adult White and African American Individuals","volume":"6","author":"Guo","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Li, L., He, X., Liu, M., Yun, L., and Cong, B. (2022). Diagnostic value of cardiac miR-126-5p, miR-134-5p, and miR-499a-5p in coronary artery disease-induced sudden cardiac death. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.944317"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1253\/circrep.CR-19-0085","article-title":"Sleep Apnea and Sudden Cardiac Death","volume":"1","author":"Blackwell","year":"2019","journal-title":"Circ. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yuan, L., Lu, L., Wang, X., Qu, M., Gao, Y., and Pan, B. (2023). Comorbid anxiety and depressive symptoms and the related factors among international medical students in China during COVID-19 pandemic: A cross-sectional study. BMC Psychiatry, 23.","DOI":"10.1186\/s12888-023-04638-7"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"58","DOI":"10.5491\/SHAW.2012.3.1.58","article-title":"Outbreak of sudden cardiac deaths in a tire manufacturing facility: Can it be caused by nanoparticles?","volume":"3","author":"Kim","year":"2012","journal-title":"Saf. Health Work."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1093\/ajh\/hpt136","article-title":"Central aortic blood pressure of hypertensive men during short-term cold exposure","volume":"27","author":"Hintsala","year":"2014","journal-title":"Am. J. Hypertens."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e017398","DOI":"10.1136\/bmjopen-2017-017398","article-title":"Risk of sudden cardiac death in relation to season-specific cold spells: A case-crossover study in Finland","volume":"7","author":"Ryti","year":"2017","journal-title":"BMJ Open"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1093\/eurheartj\/ehae711","article-title":"Low ambient temperature and incident myocardial infarction with or without obstructive coronary arteries: A Chinese nationwide study","volume":"46","author":"Huang","year":"2025","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e322","DOI":"10.1097\/EE9.0000000000000322","article-title":"Short-term exposures to temperature and risk of sudden cardiac death in women: A case-crossover analysis in the Nurses\u2019 Health Study","volume":"8","author":"Hart","year":"2024","journal-title":"Environ. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vikse, J., Henry, B.M., Roy, J., Ramakrishnan, P.K., Hsieh, W.C., Walocha, J.A., and Tomaszewski, K.A. (2016). Anatomical Variations in the Sinoatrial Nodal Artery: A Meta-Analysis and Clinical Considerations. PLoS ONE, 11, Erratum in \t\t  PLoS ONE   \t\t   2016, \t\t  11, e0150051.","DOI":"10.1371\/journal.pone.0150051"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1097\/PAF.0000000000000711","article-title":"Heart Weight Is an Independent Factor Associated With, But Is a Poor Predictor for, Sudden Cardiac Death","volume":"43","author":"Garland","year":"2022","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11883-024-01200-y","article-title":"What Causes Premature Coronary Artery Disease?","volume":"26","author":"Le","year":"2024","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.jacc.2018.07.079","article-title":"Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention","volume":"72","author":"Inouye","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1165\/rcmb.2003-0103OC","article-title":"Genome-wide search and identification of a novel gel-forming mucin MUC19\/Muc19 in glandular tissues","volume":"30","author":"Chen","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1165\/rcmb.2010-0312OC","article-title":"Cloning and characterization of human MUC19 gene","volume":"45","author":"Zhu","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1159\/000338121","article-title":"Endoplasmic reticulum stress and inflammation","volume":"30","author":"Adolph","year":"2012","journal-title":"Dig. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41569-021-00511-w","article-title":"Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases","volume":"18","author":"Ren","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1016\/j.tjnut.2023.12.035","article-title":"A Genome-Wide Interaction Study of Erythrocyte \u03c9-3 Polyunsaturated Fatty Acid Species and Memory in the Framingham Heart Study Offspring Cohort","volume":"154","author":"Annevelink","year":"2024","journal-title":"J. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122504","DOI":"10.1016\/j.lfs.2024.122504","article-title":"Cingulin family: Structure, function and clinical significance","volume":"341","author":"Su","year":"2024","journal-title":"Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1161\/ATVBAHA.115.307032","article-title":"Evidence That Cingulin Regulates Endothelial Barrier Function In Vitro and In Vivo","volume":"36","author":"Schossleitner","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1093\/cvr\/cvx226","article-title":"Endothelial permeability, LDL deposition, and cardiovascular risk factors\u2014A review","volume":"114","author":"Mundi","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00414-020-02481-z","article-title":"Sudden cardiac death-update","volume":"135","author":"Markwerth","year":"2021","journal-title":"Int. J. Legal Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_33","first-page":"651","article-title":"Implementation of a custom hardware-accelerator for short-read mapping using Burrows-Wheeler alignment","volume":"2013","author":"Waidyasooriya","year":"2013","journal-title":"Annu. Int. Conf. IEEE Eng. Med. Biol. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1093\/eurheartj\/ehw450","article-title":"Genomic prediction of coronary heart disease","volume":"37","author":"Abraham","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/ng.3396","article-title":"A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease","volume":"47","author":"Nikpay","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1101\/gr.092619.109","article-title":"Identification of deleterious mutations within three human genomes","volume":"19","author":"Chun","year":"2009","journal-title":"Genome Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","article-title":"Predicting the functional impact of protein mutations: Application to cancer genomics","volume":"39","author":"Reva","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/humu.22225","article-title":"Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models","volume":"34","author":"Shihab","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/bioinformatics\/btv009","article-title":"An integrative approach to predicting the functional effects of non-coding and coding sequence variation","volume":"31","author":"Shihab","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D971","DOI":"10.1093\/nar\/gkz829","article-title":"PGG.Han: The Han Chinese genome database and analysis platform","volume":"48","author":"Gao","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nmeth.3484","article-title":"Phenolyzer: Phenotype-based prioritization of candidate genes for human diseases","volume":"12","author":"Yang","year":"2015","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3470\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:15Z","timestamp":1760029935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":49,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083470"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083470","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,8]]}}}