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

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

Chen, H.Y. (författare): 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

Martinsson, A. (författare): 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

Thanassoulis, G. (författare): 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

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Dina, Christian (författare): CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France

Shaffer, Christian M. (författare): Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA

Levinson, Rebecca T. (författare): Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA

Helgadóttir, Anna (författare): deCODE genetics/Amgen Inc., Reykjavik, Iceland

Capoulade, Romain (författare): CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France

Munter, Hans Markus (författare): McGill University and Genome Quebec Innovation Centre, Montreal, Canada

Cairns, Benjamin J. (författare): MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

Trudsø, Linea C. (författare): Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Hoekstra, Mary (författare): 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

Burr, Hannah A. (författare): 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

Marsh, Thomas W. (författare): 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

Damrauer, Scott M. (författare): Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

Dufresne, Line (författare): Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada

Le Scouarnec, Solena (författare): CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France

Messika-Zeitoun, David (författare): Department of Cardiology, Bichat Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Division of Cardiology, University of Ottawa Heart Institute, ON, Ottawa, Canada

Ranatunga, Dilrini K. (författare): Division of Research, Kaiser Permanente of Northern California, Oakland, USA

Whitmer, Rachel A. (författare): Department of Public Health Sciences, University of California Davis, Davis, USA

Bonnefond, Amélie (författare): University Lille, Inserm, CNRS, Institut Pasteur de Lille, CHU Lille, Lille, France; Department of Metabolism, Imperial College London, London, UK

Sveinbjornsson, Garðar (författare): deCODE genetics/Amgen Inc., Reykjavik, Iceland

Daníelsen, Ragnar (författare): Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland

Arnar, David O. (författare): 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

Thorsteinsdottir, Unnur (författare): deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland

Gudbjartsson, Daníel F (författare): deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

Ghouse, Jonas (författare): Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Olesen, Morten Salling (författare): Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Christensen, Alex H. (författare): Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, Denmark

Mikkelsen, Susan (författare): Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark

Jacobsen, Rikke Louise (författare): Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Dowsett, Joseph (författare): Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Pedersen, Ole Birger Vesterager (författare): Department of Clinical Immunology, Zealand University Hospital, Naestved, Denmark

Erikstrup, Christian (författare): Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

Ostrowski, Sisse R. (författare): Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

O'Donnell, Christopher J. (författare): National Heart, Lung, Blood Institute's and Boston University's Framingham Heart Study, Boston, USA

Budoff, Matthew J. (författare): Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA

Gudnason, Vilmundur (författare): Faculty of Medicine, University of Iceland, Reykjavík, Iceland

Söderberg, Stefan (författare): Umeå universitet,Institutionen för folkhälsa och klinisk medicin

Rotter, Jerome I. (författare): Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, USA

Lathrop, Mark (författare): McGill University and Genome Quebec Innovation Centre, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada

Bundgaard, Henning (författare): Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Johansson, Bengt (författare): Umeå universitet,Institutionen för folkhälsa och klinisk medicin

Ljungberg, Johan (författare): Umeå universitet,Institutionen för folkhälsa och klinisk medicin

Näslund, Ulf (författare): Umeå universitet,Institutionen för folkhälsa och klinisk medicin

Le Tourneau, Thierry (författare): CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F, France

Smith, J. Gustav, 1982 (författare): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine

Wells, Quinn S. (författare): Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, USA

Stefánsson, Kári (författare): deCODE genetics/Amgen Inc., Reykjavik, Iceland; School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland

Schott, Jean-Jacques (författare): CHU Nantes, CNRS, INSERM, l'institut du thorax, 8 Quai Moncousu, Nantes F, France

Rader, Daniel J. (författare): Departments of Genetics and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

Clarke, Robert (författare): MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

Engert, James C. (författare): 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

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Division of Experimental Medicine, McGill University, Montreal, Canada; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Room D055120, 1001 Decarie Blvd., QC, Montreal, Canada McGill University (creator_code:org_t)

Oxford University Press, 2023
2023
Engelska 13 s.
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:21, s. 1927-1939

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Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

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.

Ämnesord

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)

Nyckelord

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

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Av författaren/redakt...: Chen, H.Y.; Martinsson, A.; Thanassoulis, G.; Dina, Christian; Shaffer, Christi ...; Levinson, Rebecc ...; visa fler...; 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.; visa färre...

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Av lärosätet: Lunds universitet; Umeå universitet; Göteborgs universitet

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