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<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P \u2264 5 \u00d7 10\u22128, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2\u2013SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26\u20131.35; P = 2.7 \u00d7 10\u221251] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08\u20131.37; P = 1.4 \u00d7 10\u22123), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g\/L of apolipoprotein B, 3.85; 95% CI, 2.90\u20135.12; P = 2.1 \u00d7 10\u221220) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17\u20131.23; P = 4.8 \u00d7 10\u221273) and body mass index (OR per kg\/m2, 1.07; 95% CI, 1.05\u20131.9; P = 1.9 \u00d7 10\u221212). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehad142","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T10:01:20Z","timestamp":1677578480000},"page":"1927-1939","source":"Crossref","is-referenced-by-count":121,"title":["Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study"],"prefix":"10.1093","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8885-7583","authenticated-orcid":false,"given":"Hao","family":"Yu Chen","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, McGill University , 1001 Decarie Blvd., Room EM1.2218, Montreal, Quebec H4A 3J1 , Canada"},{"name":"Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute , 1001 Decarie Blvd., Room D05.5120, Montreal, Quebec H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-7348","authenticated-orcid":false,"given":"Christian","family":"Dina","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , 8 Quai Moncousu, Nantes F-44000 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aeron M","family":"Small","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3165-2840","authenticated-orcid":false,"given":"Hans Markus","family":"Munter","sequence":"additional","affiliation":[{"name":"McGill University and Genome Quebec Innovation Centre , Montreal , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1461-0777","authenticated-orcid":false,"given":"Andreas","family":"Martinsson","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Clinical Sciences, Lund University, Sweden and Sk\u00e5ne University Hospital , Lund , Sweden"},{"name":"The Wallenberg Laboratory\/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital , Gothenburg , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin 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