{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:28:31Z","timestamp":1786969711227,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Heat shock proteins of the HSP70 family and their BAG co-chaperones regulate responses to oxidative stress, inflammation, apoptosis, and ischemia, all central to coronary artery disease (CAD) pathogenesis. The contribution of genetic variants within HSP70-family and BAG co-chaperone genes to CAD susceptibility remains unclear. Thus, we sought to evaluate associations of HSP70- and BAG-related SNPs with CAD risk and to characterize their potential regulatory effects using comprehensive bioinformatic analyses. A case\u2013control cohort of 834 CAD patients and 1328 controls of Russian ethnicity was genotyped for 13 SNPs. Associations with CAD susceptibility and traits were tested using log-additive regression with adaptive permutation. Loci underwent functional annotation. The C allele of BAG1 rs706121 was associated with increased CAD risk overall (OR = 1.24, pperm = 0.019), in males (OR = 1.39, pperm = 0.002), and in smokers (OR = 1.39, pperm = 0.020). BAG3 rs196329 was associated with lower risk in males (A allele: OR = 0.82, pperm = 0.040), whereas HSPA6 rs753856 was associated with reduced risk in physically active individuals (G allele: OR = 0.61, pperm = 0.008). Additional associations involved clinical or biochemical traits. Functional annotation identified potential regulatory effects, including eQTL associations, overlap with histone marks, and allele-dependent changes in transcription factor binding. HSP70 and BAG variants may contribute to CAD susceptibility and support sex- and lifestyle-informed risk assessment.<\/jats:p>","DOI":"10.3390\/ijms27167299","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Variants in HSP70 Family and BAG Co-Chaperone Genes: Associations with Coronary Artery Disease Risk and Potential Regulatory Effects"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-5901","authenticated-orcid":false,"given":"Olga","family":"Polshvedkina","sequence":"first","affiliation":[{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"},{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0652-2219","authenticated-orcid":false,"given":"Ksenia","family":"Kobzeva","sequence":"additional","affiliation":[{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0587-1609","authenticated-orcid":false,"given":"Yuriy L.","family":"Orlov","sequence":"additional","affiliation":[{"name":"Institute of Digital Biodesign and AI in Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), 119991 Moscow, Russia"},{"name":"Agrarian and Technological Institute, Patrice Lumumba Peoples\u2019 Friendship University of Russia, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-0623","authenticated-orcid":false,"given":"Olga","family":"Bushueva","sequence":"additional","affiliation":[{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia"},{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/S0140-6736(25)00055-8","article-title":"The Lancet Commission on Rethinking Coronary Artery Disease: Moving from Ischaemia to Atheroma","volume":"405","author":"Zaman","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1553","DOI":"10.1016\/S2214-109X(23)00355-8","article-title":"Global Burden of Peripheral Artery Disease and Its Risk Factors, 1990\u20132019: A Systematic Analysis for the Global Burden of Disease Study 2019","volume":"11","author":"Kim","year":"2023","journal-title":"Lancet Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cheng, D.C.Y., Climie, R.E., Shu, M., Grieve, S.M., Kozor, R., and Figtree, G.A. (2023). Vascular Aging and Cardiovascular Disease: Pathophysiology and Measurement in the Coronary Arteries. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1206156"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5551\/jat.26104","article-title":"The Cardio-Ankle Vascular Index and Ankle-Brachial Index in Young Russians","volume":"22","author":"Sorokin","year":"2015","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Singh, M.K., Shin, Y., Ju, S., Han, S., Choe, W., Yoon, K.-S., Kim, S.S., and Kang, I. (2024). Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084209"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s12017-025-08885-7","article-title":"When Heroes Fall: Reduced Expression of Heat-Resistant Obscure Proteins in Ischemic Stroke","volume":"27","author":"Dorofeeva","year":"2025","journal-title":"Neuromol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1126\/science.1057268","article-title":"Structure of a Bag\/Hsc70 Complex: Convergent Functional Evolution of Hsp70 Nucleotide Exchange Factors","volume":"291","author":"Sondermann","year":"2001","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41580-025-00890-9","article-title":"Mechanisms and Regulation of the Hsp70 Chaperone Network","volume":"27","author":"Wentink","year":"2026","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Diao, H., Wu, K., Lan, D., Wang, D., Zhao, J., Huang, B., Shao, X., Wang, R., Tan, H., and Tang, X. (2022). BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation. Genes, 13.","DOI":"10.3390\/genes13081338"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2431","DOI":"10.1038\/cddis.2016.321","article-title":"The Prosurvival Protein BAG3: A New Participant in Vascular Homeostasis","volume":"7","author":"Carrizzo","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.niox.2015.11.002","article-title":"Endothelial Nitric Oxide Synthase Induces Heat Shock Protein HSPA6 (HSP70B\u2032) in Human Arterial Smooth Muscle Cells","volume":"52","author":"McCullagh","year":"2016","journal-title":"Nitric Oxide"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bonam, S.R., Ruff, M., and Muller, S. (2019). HSPA8\/HSC70 in Immune Disorders: A Molecular Rheostat That Adjusts Chaperone-Mediated Autophagy Substrates. Cells, 8.","DOI":"10.3390\/cells8080849"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5908","DOI":"10.1038\/s41598-024-56216-w","article-title":"HSPA9 Reduction Exacerbates Symptoms and Cell Death in DSS-Induced Inflammatory Colitis","volume":"14","author":"Jang","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1161\/01.ATV.0000235720.61091.c7","article-title":"HSPA12B Is Predominantly Expressed in Endothelial Cells and Required for Angiogenesis","volume":"26","author":"Steagall","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1038\/s41467-021-23272-z","article-title":"Cardiomyocyte Contractile Impairment in Heart Failure Results from Reduced BAG3-Mediated Sarcomeric Protein Turnover","volume":"12","author":"Martin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kizilboga, T., Baskale, E.A., Yildiz, J., Akcay, I.M., Zemheri, E., Can, N.D., Ozden, C., Demir, S., Ezberci, F., and Dinler-Doganay, G. (2019). Bag-1 Stimulates Bad Phosphorylation through Activation of Akt and Raf Kinases to Mediate Cell Survival in Breast Cancer. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6477-4"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s11033-025-11014-z","article-title":"Genetic Variants in HSP40 Co-Chaperones Modulate Ischemic Heart Disease Risk","volume":"52","author":"Polshvedkina","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kobzeva, K., Ivenkov, M., Gromov, R., and Bushueva, O. (2024). HSP90 Family Members, Their Regulators and Ischemic Stroke Risk: A Comprehensive Molecular-Genetics and Bioinformatics Analysis. Front. Biosci., 16.","DOI":"10.31083\/j.fbs1604019"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"211","DOI":"10.31083\/j.jin2312211","article-title":"Polymorphism in Genes Encoding HSP40 Family Proteins Is Associated with Ischemic Stroke Risk and Brain Infarct Size: A Pilot Study","volume":"23","author":"Kobzeva","year":"2024","journal-title":"J. Integr. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.18413\/2658-6533-2024-10-2-0-1","article-title":"HSPD1 Gene Polymorphism Is Associated with an Increased Risk of Ischemic Stroke in Smokers","volume":"10","author":"Stetskaya","year":"2024","journal-title":"Res. Results Biomed."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kobzeva, K.A., Soldatova, M.O., Stetskaya, T.A., Soldatov, V.O., Deykin, A.V., Freidin, M.B., Bykanova, M.A., Churnosov, M.I., Polonikov, A.V., and Bushueva, O.Y. (2023). Association between HSPA8 Gene Variants and Ischemic Stroke: A Pilot Study Providing Additional Evidence for the Role of Heat Shock Proteins in Disease Pathogenesis. Genes, 14.","DOI":"10.3390\/genes14061171"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.ibneur.2023.05.004","article-title":"Polymorphism of SERF2, the Gene Encoding a Heat-Resistant Obscure (Hero) Protein with Chaperone Activity, Is a Novel Link in Ischemic Stroke","volume":"14","author":"Belykh","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Shilenok, I., Kobzeva, K., Deykin, A., Pokrovsky, V., Patrakhanov, E., and Bushueva, O. (2024). Obesity and Environmental Risk Factors Significantly Modify the Association between Ischemic Stroke and the Hero Chaperone C19orf53. Life, 14.","DOI":"10.3390\/life14091158"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"278","DOI":"10.18413\/2658-6533-2022-8-3-0-2","article-title":"C9orf16 (BBLN) Gene, Encoding a Member of Hero Proteins, Is a Novel Marker in Ischemic Stroke Risk","volume":"8","author":"Kobzeva","year":"2022","journal-title":"Res. Results Biomed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1161\/hc0802.103729","article-title":"Heat Shock Proteins, Inflammation, and Cardiovascular Disease","volume":"105","author":"Pockley","year":"2002","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4085\/1062-6050-47.2.184","article-title":"Heat Stress and Cardiovascular, Hormonal, and Heat Shock Proteins in Humans","volume":"47","author":"Iguchi","year":"2012","journal-title":"J. Athl. Train."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0165-2478(01)00217-6","article-title":"Immunocytochemical Detection of Fc\u03b3 Receptors in Human Atherosclerotic Lesions","volume":"77","author":"Ratcliffe","year":"2001","journal-title":"Immunol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1258\/ebm.2012.011373","article-title":"The Role of Fc\u03b3 Receptors in Atherosclerosis","volume":"237","author":"Wang","year":"2012","journal-title":"Exp. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.cyto.2013.03.020","article-title":"IL-6 and Its Receptors in Coronary Artery Disease and Acute Myocardial Infarction","volume":"62","author":"Anderson","year":"2013","journal-title":"Cytokine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1007\/s11033-012-2345-x","article-title":"IL-6 Gene Polymorphisms and CAD Risk: A Meta-Analysis","volume":"40","author":"Yang","year":"2013","journal-title":"Mol. Biol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"H2339","DOI":"10.1152\/ajpheart.00419.2020","article-title":"BAG3 Expression and Sarcomere Localization in the Human Heart Are Linked to HSF-1 and Are Differentially Affected by Sex and Disease","volume":"320","author":"Martin","year":"2021","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1001\/jamacardio.2018.2541","article-title":"Association of Variants in BAG3 with Cardiomyopathy Outcomes in African American Individuals","volume":"3","author":"Myers","year":"2018","journal-title":"JAMA Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1161\/CIRCRESAHA.110.225649","article-title":"BAG3 and Hsc70 Interact with Actin Capping Protein CapZ to Maintain Myofibrillar Integrity Under Mechanical Stress","volume":"107","author":"Hishiya","year":"2010","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Virador, V.M., Davidson, B., Czechowicz, J., Mai, A., Kassis, J., and Kohn, E.C. (2009). The Anti-Apoptotic Activity of BAG3 Is Restricted by Caspases and the Proteasome. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005136"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e77393","DOI":"10.7554\/eLife.77393","article-title":"MCMBP Promotes the Assembly of the MCM2\u20137 Hetero-Hexamer to Ensure Robust DNA Replication in Human Cells","volume":"11","author":"Saito","year":"2022","journal-title":"eLife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s10517-015-3073-8","article-title":"Association of Flavin Monooxygenase Gene E158K Polymorphism with Chronic Heart Disease Risk","volume":"159","author":"Bushueva","year":"2015","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.jash.2015.08.006","article-title":"Gender-Specific Protective Effect of the \u2212463G>A Polymorphism of Myeloperoxidase Gene against the Risk of Essential Hypertension in Russians","volume":"9","author":"Bushueva","year":"2015","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D930","DOI":"10.1093\/nar\/gkr917","article-title":"HaploReg: A Resource for Exploring Chromatin States, Conservation, and Regulatory Motif Alterations within Sets of Genetically Linked Variants","volume":"40","author":"Ward","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of Functional Variation in Personal Genomes Using RegulomeDB","volume":"22","author":"Boyle","year":"2012","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1093\/bioinformatics\/bty1010","article-title":"atSNP Search: A Web Resource for Statistically Evaluating Influence of Human Genetic Variation on Transcription Factor Binding","volume":"35","author":"Shin","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"s13742-015-0047\u20130048","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_42","doi-asserted-by":"crossref","first-page":"20240043","DOI":"10.1515\/jib-2024-0043","article-title":"Bioinformatic Analysis of the Regulatory Potential of Tagging SNPs Provides Evidence of the Involvement of Genes Encoding the Heat-Resistant Obscure (Hero) Proteins in the Pathogenesis of Cardiovascular Diseases","volume":"22","author":"Shilenok","year":"2025","journal-title":"J. Integr. Bioinform."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shilenok, I., Kobzeva, K., Soldatov, V., Deykin, A., and Bushueva, O. (2024). C11orf58 (Hero20) Gene Polymorphism: Contribution to Ischemic Stroke Risk and Interactions with Other Heat-Resistant Obscure Chaperones. Biomedicines, 12.","DOI":"10.3390\/biomedicines12112603"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"THE GTEX CONSORTIUM The GTEx Consortium Atlas of Genetic Regulatory Effects across Human Tissues","volume":"369","author":"Aguet","year":"2020","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS A J. Integr. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7299\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:07:08Z","timestamp":1786968428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7299"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,15]]},"references-count":45,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167299"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167299","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,15]]}}}