Association of Novel Genetic Loci With Circulating Fibrinogen Levels: A Genome-Wide Association Study in 6 Population-Based Cohorts

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<5.0×10−8). These included a single-nucleotide polymorphism located in the fibrinogen &bgr; 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=1.8×10−30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3×10−15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9×10−10), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04×10−8). Conclusions—Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

[1]  K. Lunetta,et al.  Methods in Genetics and Clinical Interpretation Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts , 2010 .

[2]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[3]  Judy H. Cho,et al.  Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease , 2008, Nature Genetics.

[4]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[5]  C. Desmarais,et al.  Polymorphisms of the IL1-Receptor Antagonist Gene (IL1RN) Are Associated With Multiple Markers of Systemic Inflammation , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[6]  M. Daly,et al.  Estimation of the multiple testing burden for genomewide association studies of nearly all common variants , 2008, Genetic epidemiology.

[7]  John D. Storey,et al.  Mapping the Genetic Architecture of Gene Expression in Human Liver , 2008, PLoS biology.

[8]  N. Cook,et al.  Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25,000 initially healthy american women. , 2008, Clinical chemistry.

[9]  J. Tschopp,et al.  The inflammasome: a danger sensing complex triggering innate immunity. , 2007, Current opinion in immunology.

[10]  A. Hofman,et al.  The Rotterdam Study: objectives and design update , 2007, European Journal of Epidemiology.

[11]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[12]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[13]  Meena Kumari,et al.  Lifecourse influences on health among British adults: effects of region of residence in childhood and adulthood. , 2007, International journal of epidemiology.

[14]  Qiong Yang,et al.  The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. , 2007, American journal of epidemiology.

[15]  S. Gabriel,et al.  Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[16]  H Tunstall-Pedoe,et al.  Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. , 2005, JAMA.

[17]  C. Gieger,et al.  KORA-gen - Resource for Population Genetics, Controls and a Broad Spectrum of Disease Phenotypes , 2005 .

[18]  R. Srirajaskanthan,et al.  Venous thrombosis in inflammatory bowel disease , 2005, European journal of gastroenterology & hepatology.

[19]  M. D. de Maat,et al.  A Hepatocyte Nuclear Factor-3 Site in the Fibrinogen β Promoter Is Important for Interleukin 6-induced Expression, and Its Activity Is Influenced by the Adjacent –148C/T Polymorphism* , 2005, Journal of Biological Chemistry.

[20]  I. Shapira,et al.  Inflammation-Related Erythrocyte Aggregation in Patients with Inflammatory Bowel Disease , 2005, Digestive Diseases and Sciences.

[21]  D. Levy,et al.  A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study. , 2003, Thrombosis research.

[22]  C. Bernstein,et al.  The Incidence of Deep Venous Thrombosis and Pulmonary Embolism among Patients with Inflammatory Bowel Disease: A Population-based Cohort Study , 2001, Thrombosis and Haemostasis.

[23]  T. Spector,et al.  The genetics of haemostasis: a twin study , 2001, The Lancet.

[24]  G. Abecasis,et al.  Association Analysis in a Variance Components Framework , 2001, Genetic epidemiology.

[25]  G. Fuller,et al.  Interleukin 1β inhibits interleukin 6–mediated rat γ fibrinogen gene expression , 2000 .

[26]  G. Fuller,et al.  Interleukin 1beta inhibits interleukin 6-mediated rat gamma fibrinogen gene expression. , 2000, Blood.

[27]  A. Hofman,et al.  Elevated plasma fibrinogen: cause or consequence of cardiovascular disease? , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[28]  R. Kronmal,et al.  The Cardiovascular Health Study: design and rationale. , 1991, Annals of epidemiology.

[29]  P. Allhoff,et al.  The Framingham Offspring Study , 1991 .

[30]  Aric Invest.  The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators , 1989 .

[31]  A. Folsom,et al.  The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. , 1989, American journal of epidemiology.

[32]  V. Nguyen.  Fibrinogen and risk of cardiovascular disease: Kannel WB, Wolf PA, Castelli WP, et al JAMA 258: 1183–1186 Sep 1987 , 1988 .

[33]  R. D'Agostino,et al.  Fibrinogen and risk of cardiovascular disease. The Framingham Study. , 1987, JAMA.

[34]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.

[35]  W. Kannel,et al.  The Framingham Offspring Study. Design and preliminary data. , 1975, Preventive medicine.

[36]  W. Kannel,et al.  AN APPROACH TO LONGITUDINAL STUDIES IN A COMMUNITY: THE FRAMINGHAM STUDY , 1963, Annals of the New York Academy of Sciences.

[37]  A. Clauss,et al.  Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens , 1957 .

[38]  A. Clauss.  [Rapid physiological coagulation method in determination of fibrinogen]. , 1957, Acta haematologica.