doi: 10.1161/CIRCGENETICS.108.825224
Original Articles |
Association of Novel Genetic Loci With Circulating Fibrinogen Levels
A Genome-Wide Association Study in 6 Population-Based Cohorts
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From the Department of Epidemiology (A.D., M.K., A.H., C.M.v.D., Y.S.A., J.C.W.), Erasmus Medical Center, Rotterdam, The Netherlands; National Heart, Lung, and Blood Institute Framingham Heart Study (Q.Y., M.G.L., J.M.M., S.K., A.D.J., C.J.O.), Framingham, Mass; Department of Biostatistics (A.D., Q.Y., M.-H.C.), School of Public Health, Boston University; Department of Neurology and Framingham Heart Study (M.-H.C.), Boston University, Boston, Mass; Division of Biostatistics University of Minnesota (S.B.), Minneapolis, Minn; Departments of Hematology (M.d.M.) and Internal Medicine (F.R., A.G.U.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Mathematics (M.G.L., J.M.M.), Boston University, Boston, Mass; Division of Epidemiology and Community Health (W.T., J.S.P., A.R.F.), University of Minnesota, Minneapolis, Minn; Human Genetics Center and Institute of Molecular Medicine (K.A.V., E.B.), University of Texas Health Science Center, Houston, Tex; Department of Biostatistics, University of North Carolina, Chapel Hill, NC (D.J.C.); Division of Community Health Sciences (A.R.R., D.P.S.), St George’s, University of London, London, United Kingdom; ALSPAC Laboratory (W.L.M.), University of Bristol, Bristol, United Kingdom; Division of Cardiovascular and Medical Sciences (G.D.O.L.), University of Glasgow, Royal Infirmary, Glasgow, United Kingdom; The Wellcome Trust (W.T.C.C.C.), Hinxton, Cambridge, United Kingdom; Helmholtz Zentrum München, German Research Center for Environmental Health (A.P., J.B., M.K., T.I., C.G.), Institute of Epidemiology, Neuherberg, Germany; Cardiology Division (C.J.O.), Cardiovascular Research Center (S.K.), and Center for Human Genetic Research (S.K.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Royal North Shore Hospital (G.H.T.), Sydney, Australia; Department of Internal Medicine II-Cardiology (W.K.), University of Ulm, Ulm, Germany; Department of Statistics (S.E.), Pontificia Universidad Catolica de Chile, Chile; Seattle Epidemiologic Research and Information Center (N.L.S.), the Veterans Affairs Office of Research and Development; Center for Health Studies (B.M.P.), Group Health; Departments of Biostatistics (B.M., T.L.), Epidemiology (B.M.P., N.L.S.), Health Services (B.M.P.) and Medicine (J.C.B., B.M.P.), University of Washington, Seattle, Wash; Medical Genetics Institute (K.D.T.), Cedars-Sinai Medical Center, Los Angeles, Calif; and Division of Intramural Research (A.D.J., C.J.O.), National Heart, Lung and Blood Institute, Bethesda, Md.
Correspondence to Jacqueline C. Witteman, PhD, Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands (e-mail j.witteman{at}erasmusmc.nl) or Christopher J. O'Donnell, MD, MPH, NHLBI’s Framingham Heart Study, 73 Mount Wayte Ave, Suite #2, Framingham, MA 01702 (e-mail odonnellc@nhlbi.nih.gov).
Received October 1, 2008; accepted January 5, 2009.
Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.
Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0x10–8). These included a single-nucleotide polymorphism located in the fibrinogen β chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8x10–30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3x10–15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9x10–10), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04x10–8).
Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
Key Words: genome-wide association study • fibrinogen • genes • meta-analysis
CLINICAL PERSPECTIVE
*Drs Dehghan, Yang, and Peters contributed equally to this work.
Drs Strachan, Smith, and Folsom contributed equally to this work.
Guest Editor for this article was Donna K. Arnett, PhD.
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/2/2/125/DC1.
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Circ Cardiovasc Genet 2009 2: 125-133.
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