Opin vísindi

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

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

Titill: Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis : a genome-wide study
Höfundur: Regeneron Genetics Center
Útgáfa: 2023-06-01
Tungumál: Enska
Umfang: 13
Háskóli/Stofnun: Landspitali - The National University Hospital of Iceland
Svið: Health Sciences
Deild: Cardio-Vascular Center
Faculty of Medicine
Other departments
Birtist í: European Heart Journal; 44(21)
ISSN: 0195-668X
DOI: 10.1093/eurheartj/ehad142
Efnisorð: Hjartalæknisfræði; Adiposity/genetics; Aortic Valve Stenosis/genetics; Apolipoproteins/genetics; Dyslipidemias/complications; Genetic Predisposition to Disease; Genome-Wide Association Study/methods; Humans; Inflammation; Mendelian Randomization Analysis; Obesity; Polymorphism, Single Nucleotide/genetics; Risk Factors; Aortic stenosis; Mendelian randomization; Gene expression; Genetic risk score; Phenome-wide association study; Genome-wide association study; Cardiology and Cardiovascular Medicine
URI: https://hdl.handle.net/20.500.11815/4148

Skoða fulla færslu

Tilvitnun:

Regeneron Genetics Center 2023 , ' Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis : a genome-wide study ' , European Heart Journal , vol. 44 , no. 21 , pp. 1927-1939 . https://doi.org/10.1093/eurheartj/ehad142

Útdráttur:

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.

Athugasemdir:

Funding Information: Conflict of interest Scott M. Damrauer receives research support (to the University of Pennsylvania) from RenalytixAI and personal fees from Caico Ibs, both outside the scope of the present work. SMD is also named as a co-inventor on a government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. SMD is named as a co-inventor on a Government-owned US Patent application related to the use of PDE3B inhibition for preventing cardiovascular disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. Stefan Söderberg has received speaker honoraria and consulting fees from Actelion Ltd. George Thanassoulis has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics and Silence. Morten Salling Olesen has received 5.000.000 dkrfra Sundhedsdonationer.Journalnr. 2022-0243. David O. Arnar has received travel support from Pfizer to attend the ESC 2022 Scientific Meeting in Barcelona and has stock options in Sidekick Health Digital Therapeutics. Henning Bundgaard has received lecture fees from Amgen, MSD, Sanofi-Avensis, BMS and grants from NordForsk, Innovation Fond, Denmark, The Capital Regions Research Foundation. Alex Hoerby Christensen—Novo Nordisk Foundation NNF20OC0065799. Romaine Capoulade has received an Honorarium for one lecture from Novartis. Robert Clarke has received support from BAYER (China Kadoorie Biobank). Unnur Thorsteinsdottir’s research is funded by deCODE genetics/Amgen. Daniel F. Gudbjartsson receives funds from deCODE Genetics/Amgen. Until 1 June 2022, Gudmundur Thorgeirsson was a part time employee of deCode Genetics that is owned by Amgen. Hilma Holm is an employee of deCODE genetics/Amgen Inc. Anna Helgadottir is an employee of deCODE genetics/Amgen Inc. Funding Information: Thomas W. Marsh was supported by a research award from the Fonds de Recherche du Québec—Santé. Scott M. Damrauer is supported by the US Department of Veteran Affairs (IK2-CX00180). This work does not represent the views of the US Government or the US Department of Veterans Affairs. Stefan Söderberg was supported by Hjärt-Lungfonden (grant numbers 20140799, 20120631, and 20100635), the County Council of Västerbotten (ALF, VLL-548791), Umeå University, and the Heart Foundation of Northern Sweden. J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016-0134, 2016-0315, and 2019-0526), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania County, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and the Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. George Thanassoulis is a Chercheur Boursier Clinicien—Senior from the Fonds de Recherche du Québec—Santé. George Thanassoulis and James C. Engert hold an operating grant from the Canadian Institutes for Health Research, and George Thanassoulis holds operating grants from the Heart and Stroke Foundation of Canada and the National Institutes of Health (R01 HL128550). This study was funded by grants from the Fonds de Recherche du Québec—Santé, Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada, and National Institutes of Health (R01 HL128550). The Kaiser Permanente Research Program on Genes, Environment, and Health was funded by the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from the National Institutes of Health. The University of Oxford MRC Population Health Research Unit is funded through a strategic partnership between the Medical Research Council and the University of Oxford. Staff were also supported by the British Heart Foundation and British Heart Foundation Oxford Centre for Research Excellence (RE/18/3/34214). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org . Multi-Ethnic Study of Atherosclerosis and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This research was supported by R01 HL071739. Infrastructure for the CHARGE consortium is supported in part by the NHLBI grant R01HL105756 and also supported in part by National Institute of Health contract R01HL146860. Vanderbilt University Medical Center’s BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the National Institutes of Health Grant S10RR025141; Clinical and Translational Science Award grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD07471. This work was supported by an ANR & FRM grant [13-BSV6-0011 and DCV20070409278] to Jean-Jacques Schott, by a Fédération Française de Cardiologie, a Fondation Coeur et Recherche and an Inserm Translational Research grant to Thierry Le Tourneau. Romain Capoulade is supported by a ‘Connect Talent’ research chair from Région Pays de la Loire. Cohort PREGI set up was supported by the French Regional Council of Pays-de-la-Loire (VaCaRMe program). We thank Marie Marrec and Guénola Coste for their contribution to clinical data collection and the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest) for its technical support. The D.E.S.I.R. study (providing a set of controls) has been supported by INSERM contracts with CNAMTS, Lilly, Novartis Pharma, and Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé), Cohortes Santé TGIR, the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, Société francophone du diabète, ONIVINS, Abbott, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, and Topcon. The D.E.S.I.R. Study Group. INSERM U1018: B. Balkau, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; CHU D’Angers: A. Girault; Bichat Hospital: F. Fumeron, M. Marre, R Roussel; CHU de Rennes: F. Bonnet; CNRS UMR8090, Lille: A. Bonnefond, P. Froguel; Univ Paris Descartes, UMR1153, Paris: F.Rancière Centres d’Examens de Santé: Alençon, Angers, Blois, Caen, Chateauroux, Chartres, Cholet, Le Mans, Orléans, Tours; Institute de Recherche Médecine Générale: J. Cogneau; General practitioners of the Region; Institute inter-Regional pour la Santé: C. Born, E. Caces, M. Cailleau, O Lantieri, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol. We would like to specially thank the team of the Centre d'Investigation Clinique (Xavier Duval), the Centre de Ressources Biologiques (Sarah Tubiana), Christophe Aucan from the Assistance Publique—Hôpitaux de Paris, Département de la Recherche Clinique et du Développement (DRCD) and Estelle Marcault from the Unité de Recherche Clinique Paris Nord for their help and support during all these years. The COFRASA (clinicalTrial.gov number NCT 00338676) and GENERAC (clinicalTrial.gov number NCT00647088) studies are supported by grants from the Assistance Publique—Hôpitaux de Paris (PHRC National 2005 and 2010, and PHRC regional 2007). The Copenhagen Hospital Biobank and The Danish Blood Donor Study were supported by the Novo Nordisk Foundation (grant numbers NNF14CC0001 and NNF17OC0027594). This work was further supported by The Innovation Fund Denmark (PM Heart) Nord-Forsk (project no. 90580) and the Capital Regions Research Council (No. A5920). None of the funding sources were involved in the collection, analysis, and interpretation of data, nor the writing of this paper or the decision to submit the paper for publication. Funding Information: Thomas W. Marsh was supported by a research award from the Fonds de Recherche du Québec—Santé. Scott M. Damrauer is supported by the US Department of Veteran Affairs (IK2-CX00180). This work does not represent the views of the US Government or the US Department of Veterans Affairs. Stefan Söderberg was supported by Hjärt-Lungfonden (grant numbers 20140799, 20120631, and 20100635), the County Council of Västerbotten (ALF, VLL-548791), Umeå University, and the Heart Foundation of Northern Sweden. J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016-0134, 2016-0315, and 2019-0526), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania County, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and the Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. George Thanassoulis is a Chercheur Boursier Clinicien—Senior from the Fonds de Recherche du Québec—Santé. George Thanassoulis and James C. Engert hold an operating grant from the Canadian Institutes for Health Research, and George Thanassoulis holds operating grants from the Heart and Stroke Foundation of Canada and the National Institutes of Health (R01 HL128550). This study was funded by grants from the Fonds de Recherche du Québec—Santé, Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada, and National Institutes of Health (R01 HL128550). The Kaiser Permanente Research Program on Genes, Environment, and Health was funded by the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from the National Institutes of Health. The University of Oxford MRC Population Health Research Unit is funded through a strategic partnership between the Medical Research Council and the University of Oxford. Staff were also supported by the British Heart Foundation and British Heart Foundation Oxford Centre for Research Excellence (RE/18/3/34214). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Multi-Ethnic Study of Atherosclerosis and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This research was supported by R01 HL071739. Infrastructure for the CHARGE consortium is supported in part by the NHLBI grant R01HL105756 and also supported in part by National Institute of Health contract R01HL146860. Vanderbilt University Medical Center’s BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include the National Institutes of Health Grant S10RR025141; Clinical and Translational Science Award grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD07471. This work was supported by an ANR & FRM grant [13-BSV6-0011 and DCV20070409278] to Jean-Jacques Schott, by a Fédération Française de Cardiologie, a Fondation Coeur et Recherche and an Inserm Translational Research grant to Thierry Le Tourneau. Romain Capoulade is supported by a ‘Connect Talent’ research chair from Région Pays de la Loire. Cohort PREGI set up was supported by the French Regional Council of Pays-de-la-Loire (VaCaRMe program). We thank Marie Marrec and Guénola Coste for their contribution to clinical data collection and the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest) for its technical support. The D.E.S.I.R. study (providing a set of controls) has been supported by INSERM contracts with CNAMTS, Lilly, Novartis Pharma, and Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé), Cohortes Santé TGIR, the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, Société francophone du diabète, ONIVINS, Abbott, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, and Topcon. The D.E.S.I.R. Study Group. INSERM U1018: B. Balkau, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; CHU D’Angers: A. Girault; Bichat Hospital: F. Fumeron, M. Marre, R Roussel; CHU de Rennes: F. Bonnet; CNRS UMR8090, Lille: A. Bonnefond, P. Froguel; Univ Paris Descartes, UMR1153, Paris: F.Rancière Centres d’Examens de Santé: Alençon, Angers, Blois, Caen, Chateauroux, Chartres, Cholet, Le Mans, Orléans, Tours; Institute de Recherche Médecine Générale: J. Cogneau; General practitioners of the Region; Institute inter-Regional pour la Santé: C. Born, E. Caces, M. Cailleau, O Lantieri, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol. We would like to specially thank the team of the Centre d’Investigation Clinique (Xavier Duval), the Centre de Ressources Biologiques (Sarah Tubiana), Christophe Aucan from the Assistance Publique—Hôpitaux de Paris, Département de la Recherche Clinique et du Développement (DRCD) and Estelle Marcault from the Unité de Recherche Clinique Paris Nord for their help and support during all these years. The COFRASA (clinicalTrial.gov number NCT 00338676) and GENERAC (clinicalTrial.gov number NCT00647088) studies are supported by grants from the Assistance Publique—Hôpitaux de Paris (PHRC National 2005 and 2010, and PHRC regional 2007). The Copenhagen Hospital Biobank and The Danish Blood Donor Study were supported by the Novo Nordisk Foundation (grant numbers NNF14CC0001 and NNF17OC0027594). This work was further supported by The Innovation Fund Denmark (PM Heart) Nord-Forsk (project no. 90580) and the Capital Regions Research Council (No. A5920). None of the funding sources were involved in the collection, analysis, and interpretation of data, nor the writing of this paper or the decision to submit the paper for publication. Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Skrár

Icon
Nafn: ehad142.pdf
Stærð: 8.718Mb
Skráartegund: PDF
Skoða/Opna

Þetta verk birtist í eftirfarandi safni/söfnum: