Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. (Articolo in rivista)

Type
Label
  • Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1161/CIRCULATIONAHA.113.002251 (literal)
Alternative label
  • Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD, Teumer A, Reiner AP, Folkersen L, Basu S, Rudnicka AR, Trompet S, Mälarstig A, Baumert J, Bis JC, Guo X, Hottenga JJ, Shin SY, Lopez LM, Lahti J, Tanaka T, Yanek LR, Oudot-Mellakh T, Wilson JF, Navarro P, Huffman JE, Zemunik T, Redline S, Mehra R, Pulanic D, Rudan I, Wright AF, Kolcic I, Polasek O, Wild SH, Campbell H, Curb JD, Wallace R, Liu S, Eaton CB, Becker DM, Becker LC, Bandinelli S, Räikkönen K, Widen E, Palotie A, Fornage M, Green D, Gross M, Davies G, Harris SE, Liewald DC, Starr JM, Williams FM, Grant PJ, Spector TD, Strawbridge RJ, Silveira A, Sennblad B, Rivadeneira F, Uitterlinden AG, Franco OH, Hofman A, van Dongen J, Willemsen G, Boomsma DI, Yao J, Swords Jenny N, Haritunians T, McKnight B, Lumley T, Taylor KD, Rotter JI, Psaty BM, Peters A, Gieger C, Illig T, Grotevendt A, Homuth G, Völzke H, Kocher T, Goel A, Franzosi MG, Seedorf U, Clarke R, Steri M, Tarasov KV, Sanna S, Schlessinger D, Stott DJ, Sattar N, Buckley BM, Rumley A, Lowe GD, McArdle WL, Chen MH, Tofler GH, Song J, Boerwinkle E, Folsom AR, Rose LM, Franco-Cereceda A, Teichert M, Ikram MA, Mosley TH, Bevan S, Dichgans M, Rothwell PM, Sudlow CL, Hopewell JC, Chambers JC, Saleheen D, Kooner JS, Danesh J, Nelson CP, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Morange PE, Ferrucci L, Eriksson JG, Jacobs D, Deary IJ, Soranzo N, Witteman JC, de Geus EJ, Tracy RP, Hayward C, Koenig W, Cucca F, Jukema JW, Eriksson P, Seshadri S, Markus HS, Watkins H, Samani NJ; VTE Consortium; STROKE Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); C4D Consortium; CARDIoGRAM Consortium, Wallaschofski H, Smith NL, Tregouet D, Ridker PM, Tang W, Strachan DP, Hamsten A, O'Donnell CJ. (2013)
    Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
    in Circulation (Praha)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD, Teumer A, Reiner AP, Folkersen L, Basu S, Rudnicka AR, Trompet S, Mälarstig A, Baumert J, Bis JC, Guo X, Hottenga JJ, Shin SY, Lopez LM, Lahti J, Tanaka T, Yanek LR, Oudot-Mellakh T, Wilson JF, Navarro P, Huffman JE, Zemunik T, Redline S, Mehra R, Pulanic D, Rudan I, Wright AF, Kolcic I, Polasek O, Wild SH, Campbell H, Curb JD, Wallace R, Liu S, Eaton CB, Becker DM, Becker LC, Bandinelli S, Räikkönen K, Widen E, Palotie A, Fornage M, Green D, Gross M, Davies G, Harris SE, Liewald DC, Starr JM, Williams FM, Grant PJ, Spector TD, Strawbridge RJ, Silveira A, Sennblad B, Rivadeneira F, Uitterlinden AG, Franco OH, Hofman A, van Dongen J, Willemsen G, Boomsma DI, Yao J, Swords Jenny N, Haritunians T, McKnight B, Lumley T, Taylor KD, Rotter JI, Psaty BM, Peters A, Gieger C, Illig T, Grotevendt A, Homuth G, Völzke H, Kocher T, Goel A, Franzosi MG, Seedorf U, Clarke R, Steri M, Tarasov KV, Sanna S, Schlessinger D, Stott DJ, Sattar N, Buckley BM, Rumley A, Lowe GD, McArdle WL, Chen MH, Tofler GH, Song J, Boerwinkle E, Folsom AR, Rose LM, Franco-Cereceda A, Teichert M, Ikram MA, Mosley TH, Bevan S, Dichgans M, Rothwell PM, Sudlow CL, Hopewell JC, Chambers JC, Saleheen D, Kooner JS, Danesh J, Nelson CP, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Morange PE, Ferrucci L, Eriksson JG, Jacobs D, Deary IJ, Soranzo N, Witteman JC, de Geus EJ, Tracy RP, Hayward C, Koenig W, Cucca F, Jukema JW, Eriksson P, Seshadri S, Markus HS, Watkins H, Samani NJ; VTE Consortium; STROKE Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); C4D Consortium; CARDIoGRAM Consortium, Wallaschofski H, Smith NL, Tregouet D, Ridker PM, Tang W, Strachan DP, Hamsten A, O'Donnell CJ. (literal)
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  • PROCARDIS controls: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden (M.S-L., A.S., B.S., R.S., A.H.). PROCARDIS cases: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden (A.M.); Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK, Department of Cardiovascular Medicine, The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK (A.G., H.W.); Clinical Trial Service Unit, University of Oxford, Oxford, UK (R.C.); Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy (M.G.F.); and Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany (U.S.). FHS: National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, US National Heart, Lung and Blood Institute, Division of Intramural Research, Bethesda, MD (J.H., A.D.J., C.J.O., S.S.); Royal North Shore Hospital, University of Sydney, Sydney, Australia (G.H.T.); Department of Biostatistics, Boston University, Boston, MA (M.-H.C.); and Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.). WGHS: Division of Preventive Medicine, Brigham and Women's Hospital (D.I.C., L.M.R., P.M.R.) and Harvard Medical School (D.I.C., P.M.R.), Boston, MA. SardiNIA: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy (S.N., M.S., S.S., F.C.); and Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD (K.T., D.S.). The Rotterdam Study: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (A.D., J.C.M.W., A.H., O.H.F., M.A.I.); Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (A.G.U., F.R.); Department of Radiology and Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands (M.A.I.); and Netherlands Consortium on Healthy Aging, Leiden, the Netherlands (A.D., J.C.M.W., A.H., A.G.U., F.R., O.H.F.). SHIP: Ernst-Moritz-Arndt University Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Department for Functional Genomics, Greifswald, Germany (A.T., G.H.); University Medicine Greifswald, Institute of Clinical Chemistry and Laboratory Medicine, Greifswald, Germany (A.G., H.W.); Ernst-Moritz-Arndt-University of Greifswald, Institute for Community Medicine, Section Study of Health in Pomerania (SHIP), Greifswald, Germany (H.V); and University Medicine Greifswald, Policlinics for Restorative Dentistry, Periodontology and Endodontology, Department of Periodontology, Greifswald, Germany (T.K.). CARDIA: Department of Epidemiology, University of Washington, Seattle (A.R.); Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston (M.F.); Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL (D.G.); and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN (M.G.). PROSPER/PHASE: Department of Cardiology and Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands (S.T.); Institute of Cardiovascular and Medical Sciences, School of Medicine, University of Glasgow, Glasgow, UK (D.J.S.); BHF Glasgow Cardiovascular Research Center, Faculty of Medicine, Glasgow, UK (N.S.); Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland (B.M.B.); Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands; and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (J.W.J.). CHS: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (J.C.B., B.M.P.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); Department of Biostatistics, University of Washington, Seattle (B.M., T.L.); Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA (K.D.T.); Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (J.I.R); Department of Epidemiology, University of Washington, Seattle; Seattle Epidemiological Research and Information Center, Office of Research and Development, Seattle, WA; and Group Health Research Institute, Group Health Cooperative, Seattle, WA (N.L.S.). LBC1936 and LBC1921: Center for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK (L.M.L., G.D., S.E.H., D.C.L., J.M.S., I.J.D.); Department of Psychology, University of Edinburgh, Edinburgh, UK (L.M.L., G.D., I.J.D.); Medical Genetics Section, University of Edinburgh Molecular Medicine Center, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK (S.E.H.); and Geriatric Medicine unit, University of Edinburgh, Western General Hospital, Edinburgh, UK (J.M.S.). MARTHA: Aix Marseille Université, Inserm, NORT, UMR_S 1062, Marseille, France (P.-E.M.); INSERM, UMR_S 937, Paris, France (D.-A.T., T.O.-M.); and ICAN Institute for Cardiometabolism and Nutrition, Université Pierre et Marie Curie, Paris, France (D.-A.T.). CROATIA-Split: Faculty of Medicine, University of Split, Soltanska 2, Split, Croatia (T.Z.); Division of Hematology, Department of Medicine, Clinical Hospital Center Zagreb, Zagreb, Croatia; Faculty of Medicine Osijek, J.J. Strossmayer University of Osijek, Osijek, Croatia (D.P.); and Center for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, UK (I.R.). CROATIA_Korcula: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK (J.E.H., A.F.W., C.H.). CROATIA_Vis: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK (P.N.); and Department of Public Health, University of Split Medical School, Split, Croatia (I.K., O.P.). ORCADES: Center for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, UK (H.C., S.H.W., J.F.W.). B58C: Division of Population Health Sciences and Education, St. George's, University of London, London, UK (D.P.S., A.R.R.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK (A.R., G.D.L.); and School of Social and Community Medicine, University of Bristol, Bristol, UK (W.L.M.). KORA: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (J.B.); Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Munich Heart Alliance, Munich, Germany (A.P.); Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (C.G.); Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany (T.I.); and Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany (W.K.). InCHIANTI: Clinical Research Branch, National Institute on Aging, Baltimore, MD (T.T., L.F.); and Unit, Azienda Sanitaria Firenze, Florence, Italy (S.B.). Twins UK: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK (S.-Y.S., N.S.); Department of Twin Research and Genetic Epidemiology, King's College London, London, UK (F.M.K.W., T.D.S.); Division of Cardiovascular & Diabetes Research, Leeds University, Leeds, UK (P.J.G.); and MRC Center for CAiTE, School of Social and Community Medicine, University of Bristol, Bristol, UK (S-Y.S.). HBCS: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland (J.L., K.R.); Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland (E.W.); Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland (A.P); National Institute for Health and Welfare, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; Folkhalsan Research Center, Helsinki, Finland; and Vasa Central Hospital, Vasa, Finland (J.G.E.). The Netherlands Twin Registry: Department of Biological Psychology, VU University & EMGO+ Institute, VU Medical Center, Amsterdam, the Netherlands (J.J.H.J.v.D., G.W., D.I.B., E.J.C.d.G.). ARIC: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (W.T., A.R.F.); Division of Biostatistics, University of Minnesota, Minneapolis (S.B., J.S.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); and Departments of Medicine (Geriatrics) and Neurology, University of Mississippi Medical Center, Jackson (T.H.M.). MESA: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA (J.Y.; T.H.); Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (X.G); Center for Clinical and Translational Science, University of Vermont, Burlington (R.P.T.); and Department of Pathology, University of Vermont College of Medicine, Burlington (N.S.J.). GeneSTAR: The Johns Hopkins University, School of Medicine, Division of General Internal Medicine, Baltimore, MD (L.R.Y., D.M.B., L.C.B.); and the Johns Hopkins University, School of Medicine, Division of Cardiology, Baltimore, MD (L.C.B.). WHI: Department of Epidemiology, University of Washington, Seattle; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (A.R.); Center for Primary Care and Prevention, Alpert Medical School, Brown University, Providence, RI (C.B.E.); Department of Epidemiology and Program on Genomics and Nutrition, School of Public Health, and Center for Metabolic Diseases Prevention, University of California Los Angeles (S.L.); Departments of Epidemiology and Internal Medicine, University of Iowa College of Public Health, Iowa City (R.W.); and John A. Burns School of Medicine, University of Hawaii and Pacific Health Research Institute, Honolulu, HI (J.D.C.). CSF: Department of Medicine, Harvard Medical School, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston, MA (S.R.); and Department of Medicine, Case Medical Center, Cleveland, OH (R.M.). ASAP: Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden (L.F., P.E.); and Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (A.F.-C.). C4D: Clinical Trial Service Unit, University of Oxford, Oxford, UK (J.C.H.); Department of Epidemiology & Biostatistics, Imperial College London, St. Mary's Campus, London, UK (J.C.C.); Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (J.D.); Center for Non-Communicable Diseases, Karachi, Pakistan (D.S., J.D.); Department of Biostatistics and Epidemiology and Department of Medicine, University of Pennsylvania, Philadelphia, PA (D.S.); and National Heart and Lung Institute, Imperial College London, London, UK (J.S.K.). CARDIoGRAM: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK; Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK (C.P.N., N.J.S.); Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung, Universität zu Lübeck, Lübeck, Germany (J.E., H.S.); Cardiovascular Institute, University of Pennsylvania Medical Center, Philadelphia, PA; Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.R.); Cardiovascular Research Center and Center for Human Genetic Research, Boston, MA; General Hospital and Harvard Medical School, Boston, MA; and Julius Center, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (S.K.). VTE Consortium: LITE: Division of Epidemiology, University of Minnesota, Minneapolis, MN (W.T.); Women's Genome Health Study, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (D.C.); Rotterdam Study, Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (M.T.); Heart and Vascular Health Study, Department of Epidemiology, University of Washington, Seattle; Group Health Research Institute, Group Health Cooperative, Seattle, WA; and Seattle Epidemiological Research and Information Center, Veterans Affairs Office of Research & Development, Seattle, WA (N.L.S.). WTCCC2: Stroke and Dementia Research Center, St. Georges, University of London, London, UK (S.B., H.S.M.); Institute for Stroke and Dementia Research, Klinikum der Universitaät Muänchen, Ludwig-Maximilians-Universität, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK (P.M.R.); and Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK (C.L.M.S.). (literal)
Titolo
  • Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. (literal)
Abstract
  • Background--Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results--We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10-8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions--We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism. (literal)
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