{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:18:26Z","timestamp":1785928706125,"version":"3.56.0"},"reference-count":90,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"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: Calcific aortic stenosis is the most prevalent valvular abnormality in the Western world. Factors commonly associated with calcific aortic stenosis include advanced age, male sex, hypertension, diabetes and impaired renal function. This review synthesises the existing literature on genetic associations with calcific aortic stenosis. Methods: A systematic search was conducted in the PubMed, Ovid and Cochrane libraries from inception to 21 July 2024 to identify human studies investigating the genetic factors involved in calcific aortic stenosis. From an initial pool of 1392 articles, 78 were selected for full-text review and 31 were included in the final qualitative synthesis. The risk of bias in these studies was assessed using the Newcastle Ottawa Scale. Results: Multiple genes have been associated with calcific aortic stenosis. These genes are involved in different biological pathways, including the lipid metabolism pathway (PLA, LDL, APO, PCSK9, Lp-PLA2, PONS1), the inflammatory pathway (IL-6, IL-10), the calcification pathway (PALMD, TEX41) and the endocrine pathway (PTH, VIT D, RUNX2, CACNA1C, ALPL). Additional genes such as NOTCH1, NAV1 and FADS1\/2 influence different pathways. Mechanistically, these genes may promote a pro-inflammatory and pro-calcific environment in the aortic valve itself, leading to increased osteoblastic activity and subsequent calcific degeneration of the valve. Conclusions: Numerous genetic associations contribute to calcific aortic stenosis. Recognition of these associations can enhance risk stratification for individuals and their first-degree relatives, facilitate family screening, and importantly, pave the way for targeted therapeutic interventions focusing on the identified genetic factors. Understanding these genetic factors can also lead to gene therapy to prevent calcific aortic stenosis in the future.<\/jats:p>","DOI":"10.3390\/genes15101309","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T11:34:36Z","timestamp":1728560076000},"page":"1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetics of Calcific Aortic Stenosis: A Systematic Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4005-7752","authenticated-orcid":false,"given":"Vassilios S.","family":"Vassiliou","sequence":"first","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK"},{"name":"Fitzwilliam College, University of Cambridge, Cambridge CB3 0DG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Johnson","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Langlands","sequence":"additional","affiliation":[{"name":"Institute of Continuing Education, University of Cambridge, Cambridge CB23 8AQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1534-7587","authenticated-orcid":false,"given":"Vasiliki","family":"Tsampasian","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e006339","DOI":"10.1161\/JAHA.117.006339","article-title":"Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification","volume":"6","author":"Rutkovskiy","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Henderson, D.J., Eley, L., and Chaudhry, B. (2020). New Concepts in the Development and Malformation of the Arterial Valves. J. Cardiovasc. Dev. Dis., 7.","DOI":"10.3390\/jcdd7040038"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Di Vito, A., Donato, A., Presta, I., Mancuso, T., Brunetti, F.S., Mastroroberto, P., Amorosi, A., Malara, N., and Donato, G. (2021). Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020913"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tsampasian, V., Merinopoulos, I., Ravindrarajah, T., Ring, L., Heng, E.L., Prasad, S., and Vassiliou, V.S. (2024). Prognostic Value of Cardiac Magnetic Resonance Feature Tracking Strain in Aortic Stenosis. J. Cardiovasc. Dev. Dis., 11.","DOI":"10.3390\/jcdd11010030"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1161\/CIRCULATIONAHA.119.043391","article-title":"Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990\u20132017","volume":"141","author":"Yadgir","year":"2020","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1093\/ehjci\/jeae127","article-title":"Prevalence of asymptomatic valvular heart disease in the elderly population: A community-based echocardiographic study","volume":"25","author":"Tsampasian","year":"2024","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_7","first-page":"63","article-title":"Risk factors for progression of calcific aortic stenosis and potential therapeutic targets","volume":"17","author":"Kamath","year":"2008","journal-title":"Int. J. Angiol. Off. Publ. Int. Coll. Angiol."},{"key":"ref_8","first-page":"416","article-title":"Unoperated severe aortic stenosis: Decision making in an adult UK-based population","volume":"94","author":"Badran","year":"2012","journal-title":"Ind. Mark. Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e001982","DOI":"10.1136\/openhrt-2022-001982","article-title":"Management of asymptomatic severe aortic stenosis: A systematic review and meta-analysis","volume":"9","author":"Tsampasian","year":"2022","journal-title":"Open Heart"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e028131","DOI":"10.1161\/JAHA.122.028131","article-title":"Racial and Ethnic Disparities in Aortic Stenosis","volume":"11","author":"Parikh","year":"2022","journal-title":"J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1161\/CIRCULATIONAHA.122.061451","article-title":"Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program","volume":"147","author":"Small","year":"2023","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1093\/ehjcvp\/pvad059","article-title":"Bioinformatic platforms for clinical stratification of natural history of atherosclerotic cardiovascular diseases","volume":"9","author":"Benincasa","year":"2023","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_13","unstructured":"(2024, August 01). Covidence Better Systematic Review Management. Available online: https:\/\/www.covidence.org."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13643-019-1172-8","article-title":"Risk of bias tools in systematic reviews of health interventions: An analysis of PROSPERO-registered protocols","volume":"8","author":"Farrah","year":"2019","journal-title":"Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa1109034","article-title":"Genetic associations with valvular calcification and aortic stenosis","volume":"368","author":"Thanassoulis","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1161\/CIRCGENETICS.113.000400","article-title":"Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: A prospective Mendelian randomization study and replication in a case-control cohort. Circulation","volume":"7","author":"Arsenault","year":"2014","journal-title":"Cardiovasc. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1161\/ATVBAHA.116.308761","article-title":"Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The Copenhagen General Population Study","volume":"37","author":"Kamstrup","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ozkan, U., Ozcelik, F., Yildiz, M., and Budak, M. (2019). Lipoprotein(a) Gene Polymorphism Increases a Risk Factor for Aortic Valve Calcification. J. Cardiovasc. Dev. Dis., 6.","DOI":"10.3390\/jcdd6030031"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e002617","DOI":"10.1161\/CIRCGEN.119.002617","article-title":"Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis. Circulation","volume":"12","author":"Dina","year":"2019","journal-title":"Genom. Precis. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ijcard.2018.11.094","article-title":"Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis","volume":"276","author":"Trenkwalder","year":"2019","journal-title":"Int. J. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1001\/jamacardio.2019.1581","article-title":"Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification","volume":"4","author":"Perrot","year":"2019","journal-title":"JAMA Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1161\/ATVBAHA.120.314965","article-title":"Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels\u2014Brief Report","volume":"41","author":"Hoekstra","year":"2021","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e003271","DOI":"10.1161\/CIRCGEN.120.003271","article-title":"Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic LPA Gene Expression Levels With Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses","volume":"14","author":"Guertin","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1001\/jamacardio.2020.0246","article-title":"Association of FADS1\/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis","volume":"5","author":"Chen","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1001\/jama.2014.13959","article-title":"Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis","volume":"312","author":"Smith","year":"2014","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e002711","DOI":"10.1161\/CIRCGEN.119.002711","article-title":"Genetic Determinants of Lipids and Cardiovascular Disease Outcomes: A Wide-Angled Mendelian Randomization Investigation. Circulation","volume":"12","author":"Allara","year":"2019","journal-title":"Genom. Precis. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1210\/jc.2016-1206","article-title":"PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis","volume":"101","author":"Langsted","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.jacbts.2020.05.004","article-title":"Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis","volume":"5","author":"Perrot","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1034\/j.1399-0004.2001.600511.x","article-title":"Apolipoproteins AI, B, and E polymorphisms in severe aortic valve stenosis","volume":"60","author":"Avakian","year":"2001","journal-title":"Clin. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1161\/01.CIR.0000097560.96431.3E","article-title":"Association between apolipoprotein E alleles and calcific valvular heart disease","volume":"108","author":"Novaro","year":"2003","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1136\/hrt.2005.075317","article-title":"APOE alleles are not associated with calcific aortic stenosis","volume":"92","author":"Ortlepp","year":"2006","journal-title":"Heart"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.amjcard.2011.06.050","article-title":"Replication of genetic association studies in aortic stenosis in adults","volume":"108","author":"Gaudreault","year":"2011","journal-title":"Am. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1210\/jc.2017-01049","article-title":"Effect of APOE \u03b5 Genotype on Lipoprotein(a) and the Associated Risk of Myocardial Infarction and Aortic Valve Stenosis","volume":"102","author":"Kritharides","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12944-018-0696-6","article-title":"Association between apolipoprotein B genetic polymorphism and the risk of calcific aortic stenosis in Chinese subjects, in Xinjiang, China","volume":"17","author":"Wang","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1136\/heartjnl-2020-316722","article-title":"Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans","volume":"106","author":"Perrot","year":"2020","journal-title":"Heart"},{"key":"ref_36","first-page":"123","article-title":"Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis","volume":"2","author":"Moura","year":"2012","journal-title":"Am. J. Cardiovasc. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Junco-Vicente, A., Solache-Berrocal, G., del R\u00edo-Garc\u00eda, \u00c1., Rolle-S\u00f3\u00f1ora, V., Areces, S., Mor\u00eds, C., Mart\u00edn, M., and Rodr\u00edguez, I. (2022). IL6 gene polymorphism association with calcific aortic valve stenosis and influence on serum levels of interleukin-6. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.989539"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/s41467-018-03252-6","article-title":"Genome-wide analysis yields new loci associating with aortic valve stenosis","volume":"9","author":"Helgadottir","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s41467-018-03260-6","article-title":"A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis","volume":"9","author":"Gaudreault","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Li, Z., Gaudreault, N., Arsenault, B.J., Mathieu, P., Boss\u00e9, Y., and Th\u00e9riault, S. (2020). Phenome-wide analyses establish a specific association between aortic valve PALMD expression and calcific aortic valve stenosis. Commun. Biol., 3.","DOI":"10.1038\/s42003-020-01210-x"},{"key":"ref_41","first-page":"262","article-title":"Parathyroid hormone gene variant and calcific aortic stenosis","volume":"18","author":"Schmitz","year":"2009","journal-title":"J. Heart Valve Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1136\/heart.85.6.635","article-title":"The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis","volume":"85","author":"Ortlepp","year":"2001","journal-title":"Heart"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1161\/CIRCGENETICS.115.001145","article-title":"Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease","volume":"8","author":"Droit","year":"2015","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_44","first-page":"142","article-title":"NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis","volume":"22","author":"Ducharme","year":"2013","journal-title":"J. Heart Valve Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.omtm.2022.10.009","article-title":"LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study","volume":"27","author":"Doerfler","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vassiliou, V.S., Flynn, P.D., Raphael, C.E., Newsome, S., Khan, T., Ali, A., Halliday, B., Bruengger, A.S., Malley, T., and Sharma, P. (2017). Lipoprotein(a) in patients with aortic stenosis: Insights from cardiovascular magnetic resonance. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181077"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Telyuk, P., Austin, D., Luvai, A., and Zaman, A. (2022). Lipoprotein(a): Insights for the Practicing Clinician. J. Clin. Med., 11.","DOI":"10.3390\/jcm11133673"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2105\/AJPH.41.3.279","article-title":"Epidemiological approaches to heart disease: The Framingham Study","volume":"41","author":"Dawber","year":"1951","journal-title":"Am. J. Public Health Nation\u2019s Health"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1093\/aje\/kwk115","article-title":"Age, Gene\/Environment Susceptibility-Reykjavik Study: Multidisciplinary Applied Phenomics","volume":"165","author":"Harris","year":"2007","journal-title":"Am. J. Epidemiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1093\/aje\/kwf113","article-title":"Multi-Ethnic Study of Atherosclerosis: Objectives and design","volume":"156","author":"Bild","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1365-2796.1993.tb00647.x","article-title":"The Malmo Diet and Cancer Study. Design and feasibility","volume":"233","author":"Berglund","year":"1993","journal-title":"J. Intern. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/HCO.0000000000000300","article-title":"Lipoprotein(a) and Oxidized Phospholipids in Calcific Aortic Valve Stenosis","volume":"31","author":"Yeang","year":"2016","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11883-019-0803-9","article-title":"Looking at Lp(a) and Related Cardiovascular Risk: From Scientific Evidence and Clinical Practice","volume":"21","author":"Stulnig","year":"2019","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1093\/eurheartj\/ehq386","article-title":"Lipoprotein(a) as a cardiovascular risk factor: Current status","volume":"31","author":"Nordestgaard","year":"2010","journal-title":"Eur. Heart J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1161\/CIRCULATIONAHA.115.016757","article-title":"Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic ValveCLINICAL PERSPECTIVE","volume":"132","author":"Bouchareb","year":"2015","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1093\/eurheartj\/ehx653","article-title":"Calcific aortic valve stenosis: Hard disease in the heart: A biomolecular approach towards diagnosis and treatment","volume":"39","author":"Peeters","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1359\/jbmr.2003.18.10.1842","article-title":"BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop","volume":"18","author":"Rawadi","year":"2003","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1161\/CIRCULATIONAHA.118.037184","article-title":"Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk","volume":"139","author":"Fazio","year":"2019","journal-title":"Circulation"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1001\/jamacardio.2020.0728","article-title":"An Exploratory Analysis of Proprotein Convertase Subtilisin\/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial","volume":"5","author":"Bergmark","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_60","unstructured":"(2024, August 01). NCT04968509. Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04968509."},{"key":"ref_61","unstructured":"(2024, August 01). Study Details | PCSK9 Inhibitors in the Progression of Aortic Stenosis | ClinicalTrials.gov, Available online: https:\/\/www.smartpatients.com\/trials\/NCT03051360."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1912387","article-title":"Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol","volume":"382","author":"Ray","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1056\/NEJMoa043876","article-title":"A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis","volume":"352","author":"Cowell","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.amjcard.2008.04.060","article-title":"Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg)","volume":"102","author":"Dichtl","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1056\/NEJMoa0804602","article-title":"Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis","volume":"359","author":"Pedersen","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1093\/eurheartj\/ehn172","article-title":"Association of mitral annular calcification and aortic valve morphology: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study","volume":"29","author":"Jassal","year":"2008","journal-title":"Eur. Heart J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1194\/jlr.E800008-JLR200","article-title":"PCSK9 function and physiology","volume":"49","author":"Peterson","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Beltran, R.A., Zemeir, K.J., Kimberling, C.R., Kneer, M.S., Mifflin, M.D., and Broderick, T.L. (2022). Is a PCSK9 Inhibitor Right for Your Patient? A Review of Treatment Data for Individualized Therapy. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph192416899"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"909","DOI":"10.5551\/jat.55400","article-title":"An Update on the Role of PCSK9 in Atherosclerosis","volume":"27","author":"Yurtseven","year":"2020","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jacc.2017.11.014","article-title":"NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis","volume":"71","author":"Tsimikas","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., and Landray, M. (2015). UK biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med., 12.","DOI":"10.1371\/journal.pmed.1001779"},{"key":"ref_72","first-page":"95","article-title":"EPIC-Norfolk: Study design and characteristics of the cohort. European Prospective Investigation of Cancer","volume":"80","author":"Day","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1172\/JCI118359","article-title":"Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein","volume":"96","author":"Watson","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Artiach, G., and B\u00e4ck, M. (2020). Omega-3 Polyunsaturated Fatty Acids and the Resolution of Inflammation: Novel Therapeutic Opportunities for Aortic Valve Stenosis?. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.584128"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cyto.2014.10.031","article-title":"Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy","volume":"74","author":"Saxena","year":"2015","journal-title":"Cytokine"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1136\/heartjnl-2019-314987","article-title":"Sex differences in left ventricular remodelling, myocardial fibrosis and mortality after aortic valve replacement","volume":"105","author":"Singh","year":"2019","journal-title":"Heart"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.jacbts.2023.06.004","article-title":"Palmdelphin Deficiency Evokes NF-\u03baB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling","volume":"8","author":"Han","year":"2023","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, S., Yu, H., Gao, J., Chen, J., He, P., Zhong, H., Tan, X., Staines, K.A., Macrae, V.E., and Fu, X. (2022). PALMD regulates aortic valve calcification via altered glycolysis and NF-\u03baB\u2013mediated inflammation. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101887"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gade, T.P., Motley, M.W., Beattie, B.J., Bhakta, R., Boskey, A.L., Koutcher, J.A., and Mayer-Kuckuk, P. (2011). Imaging of alkaline phosphatase activity in bone tissue. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022608"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-99788-7","article-title":"A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement","volume":"11","author":"Vassiliou","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"A1199","DOI":"10.1016\/S0735-1097(14)61199-2","article-title":"Midwall Fibrosis and Long-Term Outcome in Patients With Aortic Stenosis","volume":"63","author":"Vassiliou","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"851945","DOI":"10.1155\/2015\/851945","article-title":"Innate and Adaptive Immunity in Calcific Aortic Valve Disease","volume":"2015","author":"Mathieu","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1615\/CritRevImmunol.v32.i1.30","article-title":"Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease","volume":"32","author":"Iyer","year":"2012","journal-title":"Crit. Rev. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1161\/CIRCRESAHA.121.318011","article-title":"Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease","volume":"128","author":"Driscoll","year":"2021","journal-title":"Circ. Res."},{"key":"ref_85","first-page":"449","article-title":"Can valvular interstitial cells become true osteoblasts? A side-by-side comparison","volume":"20","author":"Monzack","year":"2011","journal-title":"J. Heart Valve Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1093\/cvr\/cvw205","article-title":"Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation","volume":"112","author":"Lin","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1056\/NEJMoa2211644","article-title":"Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B","volume":"388","author":"Pipe","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1056\/NEJMoa2214084","article-title":"Gene Therapy in Patients with the Crigler\u2013Najjar Syndrome","volume":"389","author":"Beuers","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S2213-2600(15)00245-3","article-title":"Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: A randomised, double-blind, placebo-controlled, phase 2b trial","volume":"3","author":"Alton","year":"2015","journal-title":"Lancet Respir. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/10\/1309\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:10:52Z","timestamp":1760112652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/10\/1309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,10]]},"references-count":90,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["genes15101309"],"URL":"https:\/\/doi.org\/10.3390\/genes15101309","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,10]]}}}