دورية أكاديمية
Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
| العنوان: | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. |
|---|---|
| المؤلفون: | Roychowdhury T; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA. tanmoy63@gmail.com.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA. tanmoy63@gmail.com., Klarin D; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.; VA Palo Alto Healthcare System, Palo Alto, CA, USA., Levin MG; Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Spin JM; VA Palo Alto Healthcare System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Rhee YH; VA Palo Alto Healthcare System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Deng A; VA Palo Alto Healthcare System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Headley CA; VA Palo Alto Healthcare System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Tsao NL; Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Gellatly C; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK., Zuber V; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.; UK Dementia Research Institute at Imperial College, Imperial College London, London, UK., Shen F; University of Michigan Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA., Hornsby WE; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Laursen IH; Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Verma SS; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, PA, USA., Locke AE; Regeneron Genetics Center, LLC, Tarrytown, NY, USA., Einarsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Thorleifsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Graham SE; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Dikilitas O; Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN, USA.; Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic Rochester, Rochester, MN, USA.; Mayo Clinician Investigator Training Program, Mayo Clinic Rochester, Rochester, MN, USA., Pattee JW; University of Minnesota, Minneapolis, MN, USA., Judy RL; Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Pauls-Verges F; Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain., Nielsen JB; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.; HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway., Wolford BN; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway., Brumpton BM; HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Dilmé J; Department of Vascular and Endovascular Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain., Peypoch O; Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain.; Department of Vascular and Endovascular Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain., Juscafresa LC; Vascular Surgery Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain., Edwards TL; Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Li D; Regeneron Genetics Center, LLC, Tarrytown, NY, USA., Banasik K; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Brunak S; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jacobsen RL; Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Garcia-Barrio MT; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Zhang J; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Rasmussen LM; Department of Clinical Biochemistry, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark., Lee R; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Handa A; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Wanhainen A; Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden.; Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden., Mani K; Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden., Lindholt JS; Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark., Obel LM; Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark., Strauss E; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.; Department of General and Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland., Oszkinis G; Department of General and Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland.; Department of Vascular and General Surgery, Institute of Medical Sciences, University of Opole, Opole, Poland., Nelson CP; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK., Saxby KL; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK., van Herwaarden JA; Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van der Laan SW; Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van Setten J; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Camacho M; Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain., Davis FM; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA., Wasikowski R; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA., Tsoi LC; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA., Gudjonsson JE; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA., Eliason JL; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA., Coleman DM; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA., Henke PK; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA., Ganesh SK; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA., Chen YE; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Guan W; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA., Pankow JS; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA., Pankratz N; Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA., Pedersen OB; Department of Clinical Immunology, Zealand University Hospital-Køge, Køge, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Erikstrup C; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark., Tang W; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA., Hveem K; HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway., Gudbjartsson D; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Gretarsdottir S; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Thorsteinsdottir U; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Holm H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Stefansson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Ferreira MA; Regeneron Genetics Center, LLC, Tarrytown, NY, USA., Baras A; Regeneron Genetics Center, LLC, Tarrytown, NY, USA., Kullo IJ; Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic Rochester, Rochester, MN, USA., Ritchie MD; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Christensen AH; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.; Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark., Iversen KK; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark., Eldrup N; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Vascular Surgery, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Sillesen H; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ostrowski SR; Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Bundgaard H; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Ullum H; Statens Serum Institut, Copenhagen, Denmark., Burgess S; MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Gill D; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark., Gallagher K; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA., Sabater-Lleal M; Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain.; Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden., Surakka I; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA., Jones GT; Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Bown MJ; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK., Tsao PS; VA Palo Alto Healthcare System, Palo Alto, CA, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Willer CJ; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu.; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu., Damrauer SM; Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA. damrauer@upenn.edu.; Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. damrauer@upenn.edu.; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. damrauer@upenn.edu. |
| مؤلفون مشاركون: | DiscovEHR, Regeneron Genetics Center, UK Aneurysm Growth Study, DBDS Genomic Consortium, VA Million Veteran Program |
| المصدر: | Nature genetics [Nat Genet] 2023 Nov; Vol. 55 (11), pp. 1831-1842. Date of Electronic Publication: 2023 Oct 16. |
| نوع المنشور: | Meta-Analysis; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| مواضيع طبية MeSH: | Genome-Wide Association Study* , Aortic Aneurysm, Abdominal*/genetics, Humans ; Animals ; Mice ; Proprotein Convertase 9/genetics ; Proprotein Convertase 9/metabolism ; Subtilisin ; Proprotein Convertases |
| مستخلص: | Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model. (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.) |
| References: | Stuntz, M. Modeling the burden of abdominal aortic aneurysm in the USA in 2013. Cardiology 135, 127–131 (2016). (PMID: 2730436310.1159/000446871) Summers, K. L., Kerut, E. K., Sheahan, C. M. & Sheahan, M. G. 3rd Evaluating the prevalence of abdominal aortic aneurysms in the United States through a national screening database. J. Vasc. Surg. 73, 61–68 (2021). (PMID: 3233059510.1016/j.jvs.2020.03.046) O’Donnell, T. F. X. & Schermerhorn, M. L. Abdominal aortic aneurysm screening guidelines: United States Preventative Services Task Force and Society for Vascular Surgery. J. Vasc. Surg. 71, 1457–1458 (2020). (PMID: 3233472610.1016/j.jvs.2020.01.054) Lo, R. C. & Schermerhorn, M. L. Abdominal aortic aneurysms in women. J. Vasc. Surg. 63, 839–844 (2016). (PMID: 2674767910.1016/j.jvs.2015.10.087) Pleumeekers, H. J. et al. Aneurysms of the abdominal aorta in older adults. The Rotterdam Study. Am. J. Epidemiol. 142, 1291–1299 (1995). (PMID: 750304910.1093/oxfordjournals.aje.a117596) Chaikof, E. L. et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J. Vasc. Surg. 67, 2–77 (2018). (PMID: 2926891610.1016/j.jvs.2017.10.044) Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr. & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006). (PMID: 1655452810.1056/NEJMoa054013) Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211–221 (2017). (PMID: 28538136580030810.1056/NEJMoa1612790) Gretarsdottir, S. et al. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat. Genet. 42, 692–697 (2010). (PMID: 20622881415706610.1038/ng.622) Bown, M. J. et al. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. Am. J. Hum. Genet. 89, 619–627 (2011). (PMID: 22055160321339110.1016/j.ajhg.2011.10.002) Bradley, D. T. et al. A variant in LDLR is associated with abdominal aortic aneurysm. Circ. Cardiovasc. Genet. 6, 498–504 (2013). (PMID: 2404632810.1161/CIRCGENETICS.113.000165) Jones, G. T. et al. Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci. Circ. Res. 120, 341–353 (2017). (PMID: 27899403525323110.1161/CIRCRESAHA.116.308765) Klarin, D. et al. Genetic architecture of abdominal aortic aneurysm in the Million Veteran Program. Circulation 142, 1633–1646 (2020). (PMID: 32981348758085610.1161/CIRCULATIONAHA.120.047544) Ge, T., Chen, C. Y., Ni, Y., Feng, Y. A. & Smoller, J. W. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat. Commun. 10, 1776 (2019). (PMID: 30992449646799810.1038/s41467-019-09718-5) Pers, T. H. et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015). (PMID: 2559783010.1038/ncomms6890) Finucane, H. K. et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat. Genet. 50, 621–629 (2018). (PMID: 29632380589679510.1038/s41588-018-0081-4) Davis, F. M. et al. Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms. J. Exp. Med. 218, e20201839 (2021). (PMID: 33779682800836510.1084/jem.20201839) Calderon, D. et al. Inferring relevant cell types for complex traits by using single-cell gene expression. Am. J. Hum. Genet. 101, 686–699 (2017). (PMID: 29106824567362410.1016/j.ajhg.2017.09.009) Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016). (PMID: 27141961498792410.1093/nar/gkw377) GTEx Consortium The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020). (PMID: 10.1126/science.aaz1776) Sola-Villa, D. et al. Expression and cellular localization of 15-hydroxy-prostaglandin-dehydrogenase in abdominal aortic aneurysm. PLoS ONE 10, e0136201 (2015). (PMID: 26287481454560610.1371/journal.pone.0136201) Behrendt, N. et al. A urokinase receptor-associated protein with specific collagen binding properties. J. Biol. Chem. 275, 1993–2002 (2000). (PMID: 1063690210.1074/jbc.275.3.1993) Hanssen, E., Hew, F. H., Moore, E. & Gibson, M. A. MAGP-2 has multiple binding regions on fibrillins and has covalent periodic association with fibrillin-containing microfibrils. J. Biol. Chem. 279, 29185–29194 (2004). (PMID: 1513112410.1074/jbc.M313672200) Wang, Y. et al. Histone deacetylase 7: a signalling hub controlling development, inflammation, metabolism and disease. FEBS J. 290, 2805–2832 (2023). (PMID: 3530338110.1111/febs.16437) Pinard, A., Jones, G. T. & Milewicz, D. M. Genetics of thoracic and abdominal aortic diseases. Circ. Res. 124, 588–606 (2019). (PMID: 30763214642842210.1161/CIRCRESAHA.118.312436) Roychowdhury, T. et al. Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm. Am. J. Hum. Genet. 108, 1578–1589 (2021). (PMID: 34265237845615610.1016/j.ajhg.2021.06.016) Beil, A. et al. Disclosure of clinically actionable genetic variants to thoracic aortic dissection biobank participants. BMC Med. Genomics 14, 66 (2021). (PMID: 33648514792350810.1186/s12920-021-00902-5) Renard, M. et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J. Am. Coll. Cardiol. 72, 605–615 (2018). (PMID: 30071989637836910.1016/j.jacc.2018.04.089) Elsworth, B. et al. The MRC IEU OpenGWAS data infrastructure. Preprint at bioRxiv https://doi.org/10.1101/2020.08.10.244293 (2020). Klarin, D. et al. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat. Genet. 50, 1514–1523 (2018). (PMID: 30275531652172610.1038/s41588-018-0222-9) Graham, S. E. et al. The power of genetic diversity in genome-wide association studies of lipids. Nature 600, 675–679 (2021). (PMID: 34887591873058210.1038/s41586-021-04064-3) Evangelou, E. et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 50, 1412–1425 (2018). (PMID: 30224653628479310.1038/s41588-018-0205-x) Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237–244 (2019). (PMID: 30643251635854210.1038/s41588-018-0307-5) Zuber, V., Colijn, J. M., Klaver, C. & Burgess, S. Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization. Nat. Commun. 11, 29 (2020). (PMID: 31911605694669110.1038/s41467-019-13870-3) Helgadottir, A. et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat. Genet. 48, 634–639 (2016). (PMID: 27135400913671310.1038/ng.3561) Mansouri, R. M. et al. Atheroprotective effect of human apolipoprotein A5 in a mouse model of mixed dyslipidemia. Circ. Res. 103, 450–453 (2008). (PMID: 1865804910.1161/CIRCRESAHA.108.179861) Grosskopf, I. et al. Apolipoprotein A-V modulates multiple atherogenic mechanisms in a mouse model of disturbed clearance of triglyceride-rich lipoproteins. Atherosclerosis 224, 75–83 (2012). (PMID: 2280944510.1016/j.atherosclerosis.2012.04.011) Jorgensen, A. B. et al. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur. Heart J. 34, 1826–1833 (2013). (PMID: 2324820510.1093/eurheartj/ehs431) Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017). (PMID: 2830422410.1056/NEJMoa1615664) Maegdefessel, L. et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci. Transl. Med. 4, 122ra22 (2012). (PMID: 22357537575359410.1126/scitranslmed.3003441) Wang, H. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency is protective against venous thrombosis in mice. Sci. Rep. 7, 14360 (2017). (PMID: 29084995566261410.1038/s41598-017-14307-x) Mbikay, M. et al. Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice CSK9PC57BL/6. J. Diabetes 7, 74–84 (2015). (PMID: 2454867010.1111/1753-0407.12139) Ioannou, G. N. et al. Pcsk9 deletion promotes murine nonalcoholic steatohepatitis and hepatic carcinogenesis: role of cholesterol. Hepatol. Commun. 6, 780–794 (2022). (PMID: 3481663310.1002/hep4.1858) Harrison, S. C. et al. Genetic association of lipids and lipid drug targets with abdominal aortic aneurysm: a meta-analysis. JAMA Cardiol. 3, 26–33 (2018). (PMID: 2918829410.1001/jamacardio.2017.4293) Twine, C. P. & Williams, I. M. Systematic review and meta-analysis of the effects of statin therapy on abdominal aortic aneurysms. Br. J. Surg. 98, 346–353 (2011). (PMID: 2125400610.1002/bjs.7343) O’Donnell, T. F. X. et al. Statin therapy is associated with higher long-term but not perioperative survival after abdominal aortic aneurysm repair. J. Vasc. Surg. 68, 392–399 (2018). (PMID: 29580855605781610.1016/j.jvs.2017.11.084) Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015). (PMID: 2622255910.1056/NEJMoa1400283) Forsdahl, S. H., Singh, K., Solberg, S. & Jacobsen, B. K. Risk factors for abdominal aortic aneurysms: a 7-year prospective study: the Tromso Study, 1994–2001. Circulation 119, 2202–2208 (2009). (PMID: 1936497810.1161/CIRCULATIONAHA.108.817619) Salata, K. et al. Statins reduce abdominal aortic aneurysm growth, rupture, and perioperative mortality: a systematic review and meta-analysis. J. Am. Heart Assoc. 7, e008657 (2018). (PMID: 30371297640489410.1161/JAHA.118.008657) Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). (PMID: 20616382292288710.1093/bioinformatics/btq340) Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011). (PMID: 21167468301436310.1016/j.ajhg.2010.11.011) Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). (PMID: 17701901195083810.1086/519795) Bodenhofer, U., Kothmeier, A. & Hochreiter, S. APCluster: an R package for affinity propagation clustering. Bioinformatics 27, 2463–2464 (2011). (PMID: 2173743710.1093/bioinformatics/btr406) Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015). (PMID: 25867923443036910.1038/nbt.3192) McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016). (PMID: 27268795489382510.1186/s13059-016-0974-4) Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067 (2018). (PMID: 2916566910.1093/nar/gkx1153) Weeks, E. M. et al. Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases. Nat. Genet. 55, 1267–1276 (2023). (PMID: 3744325410.1038/s41588-023-01443-6) Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). (PMID: 24830394402249110.1371/journal.pgen.1004383) Barbeira, A. N. et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun. 9, 1825 (2018). (PMID: 29739930594082510.1038/s41467-018-03621-1) Spin, J. M. et al. Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol. Genomics 43, 993–1003 (2011). (PMID: 21712436318073510.1152/physiolgenomics.00044.2011) Maegdefessel, L. et al. miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat. Commun. 5, 5214 (2014). (PMID: 2535839410.1038/ncomms6214) Biros, E. et al. Differential gene expression in human abdominal aortic aneurysm and aortic occlusive disease. Oncotarget 6, 12984–12996 (2015). (PMID: 25944698453699310.18632/oncotarget.3848) Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). (PMID: 25642630449576910.1038/ng.3211) Sriram, V. et al. NETMAGE: a human disease phenotype map generator for the network-based visualization of phenome-wide association study results. GigaScience 11, giac002 (2022). (PMID: 35166337884831410.1093/gigascience/giac002) Bastian, M., Heymann, S. & Jacomy, M. Gephi: an open source software for exploring and manipulating networks. Proceedings of the International AAAI Conference on Web and Social Media Vol. 3, pp. 361–362 (2009). Blondel, V. D., Guillaume, J.-L., Lambiotte, R. & Lefebvre, E. Fast unfolding of communities in large networks. J. Stat. Mech. 2008, P10008 (2008). (PMID: 10.1088/1742-5468/2008/10/P10008) 1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015). Levin, M. G. et al. Prioritizing the role of major lipoproteins and subfractions as risk factors for peripheral artery disease. Circulation 144, 353–364 (2021). (PMID: 34139859832371210.1161/CIRCULATIONAHA.121.053797) Nyholt, D. R. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769 (2004). (PMID: 14997420118195410.1086/383251) Zheng, J. et al. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nat. Genet. 52, 1122–1131 (2020). (PMID: 32895551761046410.1038/s41588-020-0682-6) Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018). (PMID: 29846171597643410.7554/eLife.34408) Foley, C. N. et al. A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits. Nat. Commun. 12, 764 (2021). (PMID: 33536417785863610.1038/s41467-020-20885-8) |
| معلومات مُعتمدة: | R01 HL166991 United States HL NHLBI NIH HHS; K24 HL137010 United States HL NHLBI NIH HHS; R01 HL109946 United States HL NHLBI NIH HHS; R01 HL059367 United States HL NHLBI NIH HHS; R35 HL135824 United States HL NHLBI NIH HHS; R35 HL161016 United States HL NHLBI NIH HHS; T32 HL098049 United States HL NHLBI NIH HHS; IK2 CX001780 United States CX CSRD VA; IK2 BX005759 United States BX BLRD VA; I01 BX003362 United States BX BLRD VA; United Kingdom WT_ Wellcome Trust; CH/F/22/90014 United Kingdom BHF_ British Heart Foundation; T32 HL007843 United States HL NHLBI NIH HHS; U01 HG011710 United States HG NHGRI NIH HHS; MR/W029790/1 United Kingdom MRC_ Medical Research Council; I01 BX005831 United States BX BLRD VA; MR/S019669/1 United Kingdom MRC_ Medical Research Council; U01 HG006379 United States HG NHGRI NIH HHS; R01 HL142023 United States HL NHLBI NIH HHS; R01 HL155209 United States HL NHLBI NIH HHS; R01 HL103695 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Investigator: F Dudbridge; NJ Samani |
| المشرفين على المادة: | EC 3.4.21.- (PCSK9 protein, human) EC 3.4.21.- (Proprotein Convertase 9) EC 3.4.21.62 (Subtilisin) EC 3.4.21.- (Proprotein Convertases) |
| تواريخ الأحداث: | Date Created: 20231016 Date Completed: 20231110 Latest Revision: 20240714 |
| رمز التحديث: | 20240714 |
| مُعرف محوري في PubMed: | PMC10632148 |
| DOI: | 10.1038/s41588-023-01510-y |
| PMID: | 37845353 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder كن أول من يترك تعليقا!