Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

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Chen, H.Y.Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada,McGill University,deCODE genetics/Amgen Inc., Reykjavik, Iceland (author)

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

Article/chapterEnglish2023

Publisher, publication year, extent ...

Oxford University Press,2023
13 s.

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LIBRIS-ID:oai:lup.lub.lu.se:5b40fead-5154-492c-8e40-449f31b7e0e5
https://lup.lub.lu.se/record/5b40fead-5154-492c-8e40-449f31b7e0e5URI
https://doi.org/10.1093/eurheartj/ehad142DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-209555URI
https://gup.ub.gu.se/publication/325062URI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype
Subject category:ref swepub-contenttype

Notes

Aims 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. Methods and results 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 ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1, 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), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), 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, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
Aortic stenosis
Gene expression
Genetic risk score
Genome-wide association study
Mendelian randomization
Phenome-wide association study
Adiposity
Aortic Valve Stenosis
Apolipoproteins
Dyslipidemias
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammation
Mendelian Randomization Analysis
Obesity
Polymorphism, Single Nucleotide
Risk Factors
actin related protein 2
alkaline phosphatase
apolipoprotein B
C reactive protein
calcium
gamma glutamyltransferase
interleukin 6
lipoprotein
lipoprotein A
low density lipoprotein cholesterol
Notch4 receptor
sortilin
triacylglycerol
apolipoprotein
aortic stenosis
aortic valve
area under the curve
Article
body mass
calcification
cohort analysis
coronary artery disease
differential gene expression
dyslipidemia
fasting blood glucose level
gene expression
gene linkage disequilibrium
gene locus
gene ontology
gene set enrichment analysis
genetic risk score
genome-wide association study
human
inflammation
KEGG
lipid metabolism
logistic regression analysis
major clinical study
Mendelian randomization analysis
obesity
pathogenicity
phenome wide association study
phenotype
quality control
receiver operating characteristic
risk factor
single nucleotide polymorphism
smoking
systolic blood pressure
adipose tissue inflammation
aortic valve stenosis
complication
genetic predisposition
genetics
meta analysis
procedures
Aortic stenosis

Added entries (persons, corporate bodies, meetings, titles ...)

Martinsson, A.Gothenburg University,Göteborgs universitet,Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA,Department of Cardiology, Clinical Sciences, Lund University, Sweden; Skåne University Hospital, Lund, Sweden; Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xmands (author)
Thanassoulis, G.Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada,McGill University (author)
Dina, ChristianCHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France (author)
Shaffer, Christian M.Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA (author)
Levinson, Rebecca T.Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA (author)
Helgadóttir, AnnadeCODE genetics/Amgen Inc., Reykjavik, Iceland (author)
Capoulade, RomainCHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France (author)
Munter, Hans MarkusMcGill University and Genome Quebec Innovation Centre, Montreal, Canada (author)
Cairns, Benjamin J.MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (author)
Trudsø, Linea C.Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Hoekstra, MaryDivision of Experimental Medicine, McGill University, Room EM1.2218, 1001 Decarie Blvd., QC, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada (author)
Burr, Hannah A.Division of Experimental Medicine, McGill University, Room EM1.2218, 1001 Decarie Blvd., QC, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada (author)
Marsh, Thomas W.Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada (author)
Damrauer, Scott M.Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA (author)
Dufresne, LinePreventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada (author)
Le Scouarnec, SolenaCHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France (author)
Messika-Zeitoun, DavidDepartment of Cardiology, Bichat Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Division of Cardiology, University of Ottawa Heart Institute, ON, Ottawa, Canada (author)
Ranatunga, Dilrini K.Division of Research, Kaiser Permanente of Northern California, Oakland, USA (author)
Whitmer, Rachel A.Department of Public Health Sciences, University of California Davis, Davis, USA (author)
Bonnefond, AmélieUniversity Lille, Inserm, CNRS, Institut Pasteur de Lille, CHU Lille, Lille, France; Department of Metabolism, Imperial College London, London, UK (author)
Sveinbjornsson, GarðardeCODE genetics/Amgen Inc., Reykjavik, Iceland (author)
Daníelsen, RagnarInternal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland (author)
Arnar, David O.deCODE genetics/Amgen Inc., Reykjavik, Iceland; Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (author)
Thorsteinsdottir, UnnurdeCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (author)
Gudbjartsson, Daníel FdeCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland (author)
Ghouse, JonasLaboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Olesen, Morten SallingLaboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Christensen, Alex H.Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, Denmark (author)
Mikkelsen, SusanDepartment of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark (author)
Jacobsen, Rikke LouiseDepartment of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Dowsett, JosephDepartment of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Pedersen, Ole Birger VesteragerDepartment of Clinical Immunology, Zealand University Hospital, Naestved, Denmark (author)
Erikstrup, ChristianDepartment of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (author)
Ostrowski, Sisse R.Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (author)
O'Donnell, Christopher J.National Heart, Lung, Blood Institute's and Boston University's Framingham Heart Study, Boston, USA (author)
Budoff, Matthew J.Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA (author)
Gudnason, VilmundurFaculty of Medicine, University of Iceland, Reykjavík, Iceland (author)
Söderberg, StefanUmeå universitet,Institutionen för folkhälsa och klinisk medicin(Swepub:umu)stso0001 (author)
Rotter, Jerome I.Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA (author)
Lathrop, MarkMcGill University and Genome Quebec Innovation Centre, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada (author)
Bundgaard, HenningDepartment of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (author)
Johansson, BengtUmeå universitet,Institutionen för folkhälsa och klinisk medicin(Swepub:umu)bejo0003 (author)
Ljungberg, JohanUmeå universitet,Institutionen för folkhälsa och klinisk medicin(Swepub:umu)jonljg02 (author)
Näslund, UlfUmeå universitet,Institutionen för folkhälsa och klinisk medicin(Swepub:umu)ulna0002 (author)
Le Tourneau, ThierryCHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France (author)
Smith, J. Gustav,1982Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsmigu (author)
Wells, Quinn S.Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA (author)
Stefánsson, KárideCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (author)
Schott, Jean-JacquesCHU Nantes, CNRS, INSERM, l'institut du thorax, 8 Quai Moncousu, Nantes F, France (author)
Rader, Daniel J.Departments of Genetics and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA (author)
Clarke, RobertMRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (author)
Engert, James C.Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada (author)
Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D05.5120, 1001 Decarie Blvd., QC, Montreal, CanadaMcGill University (creator_code:org_t)
Therapeutic targets for AoRtic stenosis using GEneTics (TARGET) Consortium

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By the author/editor: Chen, H.Y.; Martinsson, A.; Thanassoulis, G.; Dina, Christian; Shaffer, Christi ...; Levinson, Rebecc ...; show more...; Helgadóttir, Ann ...; Capoulade, Romai ...; Munter, Hans Mar ...; Cairns, Benjamin ...; Trudsø, Linea C.; Hoekstra, Mary; Burr, Hannah A.; Marsh, Thomas W.; Damrauer, Scott ...; Dufresne, Line; Le Scouarnec, So ...; Messika-Zeitoun, ...; Ranatunga, Dilri ...; Whitmer, Rachel ...; Bonnefond, Améli ...; Sveinbjornsson, ...; Daníelsen, Ragna ...; Arnar, David O.; Thorsteinsdottir ...; Gudbjartsson, Da ...; Ghouse, Jonas; Olesen, Morten S ...; Christensen, Ale ...; Mikkelsen, Susan; Jacobsen, Rikke ...; Dowsett, Joseph; Pedersen, Ole Bi ...; Erikstrup, Chris ...; Ostrowski, Sisse ...; O'Donnell, Chris ...; Budoff, Matthew ...; Gudnason, Vilmun ...; Söderberg, Stefa ...; Rotter, Jerome I ...; Lathrop, Mark; Bundgaard, Henni ...; Johansson, Bengt; Ljungberg, Johan; Näslund, Ulf; Le Tourneau, Thi ...; Smith, J. Gustav ...; Wells, Quinn S.; Stefánsson, Kári; Schott, Jean-Jac ...; Rader, Daniel J.; Clarke, Robert; Engert, James C.; show less...

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