{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:23:43Z","timestamp":1792844623649,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009664","name":"Sociedad Espa\u00f1ola de Cardiolog\u00eda","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009664","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011941","name":"Gobierno del Principado de Asturias","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011941","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Aortic valve stenosis is the most frequent valve disease in developed countries and its prevalence will increase with population aging. There is still no pharmaceutical treatment nor biomarker to determine the susceptibility to develop aortic stenosis. Therefore, we analyzed the association of polymorphisms in risk loci with calcific aortic stenosis. Patients with aortic valve disease were genotyped for <jats:italic>PALMD<\/jats:italic> rs6702619, <jats:italic>LPA<\/jats:italic> rs10455872, and <jats:italic>IL6<\/jats:italic> rs1800795 polymorphisms and circulating levels of interleukin-6 (IL-6) were measured. Calcium content of leaflets obtained in valve replacement surgeries was determined by micro-computed tomography. In the genotyping of 578 individuals, we found significant association between <jats:italic>PALMD<\/jats:italic> and <jats:italic>IL6<\/jats:italic> polymorphisms and aortic stenosis in patients with tricuspid aortic valve, independently of other potentially confounding variables such as age and dyslipidemia. There was no association of these polymorphisms with valve calcium content, but this value correlated with the mean aortic pressure gradient (<jats:italic>r<\/jats:italic> = 0.44; <jats:italic>P<\/jats:italic> &amp;lt; 0.001). The CC genotype of <jats:italic>IL6<\/jats:italic> polymorphism was associated with higher levels of serum IL-6 compared to other genotypes (23.5 vs. 10.5 pg\/ml, respectively; <jats:italic>P<\/jats:italic> = 0.029). Therefore, patients carrying the CC genotype of <jats:italic>IL6<\/jats:italic> rs1800795 polymorphism present higher levels of circulating IL-6 and this could contribute to the severity of the aortic valve stenosis. Our results agree with the identification of <jats:italic>IL6<\/jats:italic> as a locus risk for stenosis and also with the intervention of this cytokine in aortic valve calcification. A more exhaustive follow-up of those patients carrying risk genotypes is therefore recommended.<\/jats:p>","DOI":"10.3389\/fcvm.2022.989539","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T07:22:19Z","timestamp":1666250539000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["IL6 gene polymorphism association with calcific aortic valve stenosis and influence on serum levels of interleukin-6"],"prefix":"10.3389","volume":"9","author":[{"given":"Alejandro","family":"Junco-Vicente","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Solache-Berrocal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"del R\u00edo-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Rolle-S\u00f3\u00f1ora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Areces","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Mor\u00eds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/j.ijcard.2014.08.053","article-title":"The prevalence of aortic stenosis in the elderly in iceland and predictions for the coming decades: the ages-reykjavik study.","volume":"176","author":"Danielsen","year":"2014","journal-title":"Int J Cardiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.jacc.2015.05.066","article-title":"Calcification in aortic stenosis: the skeleton key.","volume":"66","author":"Pawade","year":"2015","journal-title":"J Am Coll Cardiol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab395","article-title":"2021 ESC\/Eacts guidelines for the management of valvular heart disease.","volume":"43","author":"Vahanian","year":"2021","journal-title":"Eur Heart J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1093\/eurheartj\/ehab757","article-title":"Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy.","volume":"43","author":"Kraler","year":"2021","journal-title":"Eur Heart J."},{"key":"B5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.yjmcc.2019.05.016","article-title":"Development of calcific aortic valve disease: do we know enough for new clinical trials?","volume":"132","author":"Kostyunin","year":"2019","journal-title":"J Mol Cell Cardiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1056\/NEJMoa0804602","article-title":"Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.","volume":"359","author":"Rossebo","year":"2008","journal-title":"N Engl J Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1161\/CIRCULATIONAHA.109.900027","article-title":"Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (Astronomer) trial.","volume":"121","author":"Chan","year":"2010","journal-title":"Circulation."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e110","DOI":"10.1097\/MJT.0b013e3181a2b1a6","article-title":"Statin therapy and aortic stenosis: a systematic review of the effects of statin therapy on aortic stenosis.","volume":"17","author":"Loomba","year":"2010","journal-title":"Am J Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1161\/CIRCULATIONAHA.121.053708","article-title":"Effect of denosumab or alendronic acid on the progression of aortic stenosis: a double-blind randomized controlled trial.","volume":"143","author":"Pawade","year":"2021","journal-title":"Circulation."},{"key":"B10","doi-asserted-by":"publisher","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.","volume":"12","author":"Theriault","year":"2019","journal-title":"Circ Genom Precis Med."},{"key":"B11","doi-asserted-by":"publisher","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":"Theriault","year":"2018","journal-title":"Nat Commun."},{"key":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","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":"Guauque-Olarte","year":"2015","journal-title":"Circ Cardiovasc Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1093\/eurheartj\/ehs109","article-title":"Guidelines on the management of valvular heart disease (Version 2012).","volume":"33","author":"Vahanian","year":"2012","journal-title":"Eur Heart J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1016\/j.jacc.2012.11.070","article-title":"Outcome of combined stenotic and regurgitant aortic valve disease.","volume":"61","author":"Zilberszac","year":"2013","journal-title":"J Am Coll Cardiol."},{"key":"B16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.4321\/S1889-836X2016000400003","article-title":"The association of Mmp1 1g>2g polymorphism with aortic valve calcification.","volume":"8","author":"Solache-Berrocal","year":"2016","journal-title":"Rev Osteoporos Metab Miner."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13027","article-title":"Variants in cardiac gata genes associated with bicuspid aortic valve.","volume":"48","author":"Alonso-Montes","year":"2018","journal-title":"Eur J Clin Invest."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010029","article-title":"Correlation of micro-computed tomography assessment of valvular mineralisation with histopathological and immunohistochemical features of calcific aortic valve disease.","volume":"9","author":"Solache-Berrocal","year":"2019","journal-title":"J Clin Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the asbmr histomorphometry nomenclature committee.","volume":"28","author":"Dempster","year":"2013","journal-title":"J Bone Miner Res."},{"key":"B20","year":"2021","journal-title":"R: A Language and Environment for Statistical Computing."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1007\/s00011-021-01505-7","article-title":"Association of interleukin 6 \u2212174 G\/C polymorphism with coronary artery disease and circulating il-6 levels: a systematic review and meta-analysis.","volume":"70","author":"Rai","year":"2021","journal-title":"Inflamm Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"18138","DOI":"10.1074\/jbc.M000379200","article-title":"Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation.","volume":"275","author":"Terry","year":"2000","journal-title":"J Biol Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1093\/hmg\/ddab023","article-title":"Genome-wide association study of circulating interleukin 6 levels identifies novel loci.","volume":"30","author":"Ahluwalia","year":"2021","journal-title":"Hum Mol Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1146\/annurev.immunol.15.1.797","article-title":"Gp130 and the interleukin-6 family of cytokines.","volume":"15","author":"Taga","year":"1997","journal-title":"Annu Rev Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.yjmcc.2014.02.014","article-title":"P2y2 receptor represses Il-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease.","volume":"72","author":"El Husseini","year":"2014","journal-title":"J Mol Cell Cardiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1161\/ATVBAHA.112.300504","article-title":"Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells.","volume":"33","author":"Mahler","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1159\/000350896","article-title":"Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease.","volume":"81","author":"Cote","year":"2014","journal-title":"Pathobiology."},{"key":"B28","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1136\/hrt.2010.198853","article-title":"Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction.","volume":"97","author":"Cueff","year":"2011","journal-title":"Heart."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.117.007146","article-title":"Computed tomography aortic valve calcium scoring in patients with aortic stenosis.","volume":"11","author":"Pawade","year":"2018","journal-title":"Circ Cardiovasc Imaging."},{"key":"B30","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.ijcard.2011.12.098","article-title":"Association of interleukin-6 circulating levels with coronary artery disease: a meta-analysis implementing mendelian randomization approach.","volume":"157","author":"Niu","year":"2012","journal-title":"Int J Cardiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"615","DOI":"10.26402\/jpp.2018.4.12","article-title":"Serum Rantes, transforming growth factor-beta1 and interleukin-6 levels correlate with cardiac muscle fibrosis in patients with aortic valve stenosis.","volume":"69","author":"Podolec","year":"2018","journal-title":"J Physiol Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1016\/j.jacc.2010.03.019","article-title":"Associations of long-term and early adult atherosclerosis risk factors with aortic and mitral valve calcium.","volume":"55","author":"Thanassoulis","year":"2010","journal-title":"J Am Coll Cardiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1161\/CIRCGENETICS.108.820795","article-title":"Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves.","volume":"2","author":"Bosse","year":"2009","journal-title":"Circ Cardiovasc Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1007\/s10753-012-9579-6","article-title":"Inflammation is associated with the remodeling of calcific aortic valve disease.","volume":"36","author":"Cote","year":"2013","journal-title":"Inflammation."},{"key":"B35","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1210\/jc.2002-020092","article-title":"Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of c-reactive protein and markers of bone resorption in postmenopausal women.","volume":"88","author":"Ferrari","year":"2003","journal-title":"J Clin Endocrinol Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1002\/ejhf.2361","article-title":"Plasma biomarkers associated with adverse outcomes in patients with calcific aortic stenosis.","volume":"23","author":"Vidula","year":"2021","journal-title":"Eur J Heart Fail."},{"key":"B37","doi-asserted-by":"publisher","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":"B38","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1161\/CIRCULATIONAHA.121.054182","article-title":"Palmdelphin regulates nuclear resilience to mechanical stress in the endothelium.","volume":"144","author":"Sainz-Jaspeado","year":"2021","journal-title":"Circulation."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101887","article-title":"Palmd regulates aortic valve calcification via altered glycolysis and Nf-Kappab-mediated inflammation.","volume":"298","author":"Wang","year":"2022","journal-title":"J Biol Chem."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102241","article-title":"Enhancer-associated aortic valve stenosis risk locus 1p21.2 Alters Nfatc2 binding site and promotes fibrogenesis.","volume":"24","author":"Chignon","year":"2021","journal-title":"iScience."},{"key":"B41","doi-asserted-by":"publisher","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":"B42","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1001\/jama.2009.801","article-title":"Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.","volume":"301","author":"Kamstrup","year":"2009","journal-title":"JAMA."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.1056\/NEJMoa0902604","article-title":"Genetic variants associated with Lp(a) lipoprotein level and coronary disease.","volume":"361","author":"Clarke","year":"2009","journal-title":"N Engl J Med."},{"key":"B44","doi-asserted-by":"publisher","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.","volume":"7","author":"Arsenault","year":"2014","journal-title":"Circ Cardiovasc Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.jacc.2013.09.038","article-title":"Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.","volume":"63","author":"Kamstrup","year":"2014","journal-title":"J Am Coll Cardiol."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.989539\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T07:22:27Z","timestamp":1666250547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.989539\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":45,"alternative-id":["10.3389\/fcvm.2022.989539"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.989539","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,20]]},"article-number":"989539"}}