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Thromb Haemost 2008; 99(02): 388-395
DOI: 10.1160/TH07-08-0523
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults

The Cardiovascular Health Study
Cara L. Carty
1   Department of Epidemiology, University of Washington, Seattle, Washington, USA
,
Mary Cushman
2   Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Daniel Jones
2   Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Leslie A. Lange
3   Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
,
Lucia A. Hindorff
1   Department of Epidemiology, University of Washington, Seattle, Washington, USA
,
Kenneth Rice
4   Department of Biostatistics, University of Washington, Seattle, Washington, USA
,
Nancy S. Jenny
1   Department of Epidemiology, University of Washington, Seattle, Washington, USA
,
J. Peter Durda
2   Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Jeremy Walston
2   Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Christopher S. Carlson
5   Center on Aging and Health, Johns Hopkins University, Baltimore, Maryland, USA
,
Debbie Nickerson
6   Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
,
Russell P. Tracy
7   Department of Genome Sciences, University of Washington, Seattle, Washington, USA
,
Alex P. Reiner
2   Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA
› Author Affiliations
Further Information

Publication History

Received: 27 August 2007

Accepted after major revision: 23 January 2007

Publication Date:
24 November 2017 (online)

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Summary

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (≥ 5% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European-(EA) and African-descent (AA) adults (≥ 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807,FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437;each additional copy of the minor allele was associated with 13 mg/dl (95%CI: 9–16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR=1.9 (95%CI: 1.3–2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

Keywords

Fibrinogen - epidemiological studies - atherosclerosis - single nucleotide polymorphisms

 

  • References

  • 1 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
    PubMedGoogle Scholar
  • 2 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-963.
    CrossrefPubMedGoogle Scholar
  • 3 Kannel WB, Wolf PA, Castelli WP. et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. J Am Med Assoc 1987; 258: 1183-1186.
    CrossrefPubMedGoogle Scholar
  • 4 Tracy RP, Bovill EG, Yanez D. et al. Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1995; 15: 1269-1279.
    CrossrefPubMedGoogle Scholar
  • 5 Tracy RP, Arnold AM, Ettinger W. et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: Results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 1776-1783.
    CrossrefPubMedGoogle Scholar
  • 6 Jenny NS, Yanez ND, Psaty BM. et al. Inflammation biomarkers and near-term death in older men. Am J Epidemiol 2007; 165: 684-695.
    CrossrefPubMedGoogle Scholar
  • 7 de Maat MP. Effects of diet, drugs, and genes on plasma fibrinogen levels. Ann NY Acad Sci 2001; 936: 509-521.
    PubMedGoogle Scholar
  • 8 Cushman M, Yanez D, Psaty BM. et al. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. Am J Epidemiol 1996; 143: 665-676.
    CrossrefPubMedGoogle Scholar
  • 9 Yang Q, Tofler GH, Cupples LA. et al. A genomewide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study. Thromb Res 2003; 110: 57-64.
    CrossrefPubMedGoogle Scholar
  • 10 Reed T, Tracy RP, Fabsitz RR. Minimal genetic influences on plasma fibrinogen level in adult males in the NHLBI twin study. Clinical Genetics 1994; 45: 71-77.
    PubMedGoogle Scholar
  • 11 Bladbjerg EM, de Maat MP, Christensen K. et al. Genetic influence on thrombotic risk markers in the elderly--a Danish twin study. J Thromb Haemost 2006; 4: 599-607.
    CrossrefPubMedGoogle Scholar
  • 12 Simmonds R, Hermida J, Rezende S. et al. Haemostatic genetic risk factors in arterial thrombosis. Thromb Haemost 2001; 86: 374-385.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Reiner AP, Carty CL, Carlson CS. et al. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study. J Thromb Haemost 2006; 4: 1279-1287.
    CrossrefPubMedGoogle Scholar
  • 14 O'Leary DH, Polak JF, Kronmal RA. et al. Carotidartery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999; 340: 14-22.
    CrossrefPubMedGoogle Scholar
  • 15 Fried LP, Borhani NO, Enright P. et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991; 1: 263-276.
    CrossrefPubMedGoogle Scholar
  • 16 Cushman M, Cornell ES, Howard PR. et al. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem 1995; 41: 264-720.
    PubMedGoogle Scholar
  • 17 O'Leary DH, Polak JF, Wolfson Jr. SK. et al. Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke 1991; 22: 1155-1163.
    CrossrefPubMedGoogle Scholar
  • 18 Ives DG, Fitzpatrick AL, Bild DE. et al. Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. Ann Epidemiol 1995; 5: 278-285.
    CrossrefPubMedGoogle Scholar
  • 19 SeattleSNPs. NHLBI Program for Genomic Applications, UW-FHCRC, Seattle, WA. Available at http://pga.gs.washington.edu/ accessed September 2006.
    PubMed
  • 20 Collins FS, Brooks LD, Chakravarti A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res 1998; 8: 1229-1231.
    CrossrefPubMedGoogle Scholar
  • 21 Carlson CS, Eberle MA, Rieder MJ. et al. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004; b 74: 106-120.
    CrossrefPubMedGoogle Scholar
  • 22 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; b 68: 978-989.
    CrossrefPubMedGoogle Scholar
  • 23 Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7: 781-791.
    CrossrefPubMedGoogle Scholar
  • 24 Reiner AP, Ziv E, Lind DL. et al. Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. Am J Hum Genet 2005; 76: 463-477.
    CrossrefPubMedGoogle Scholar
  • 25 Nyholt D. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004; 74: 765-769.
    CrossrefPubMedGoogle Scholar
  • 26 French B, Lumley T, Monks S. et al. Simple estimates of haplotype relative risks in case-control data. Genet Epidemiol 2006; 30: 485-494.
    CrossrefPubMedGoogle Scholar
  • 27 Kathiresan S, Yang Q, Larson MG. et al. Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk. Arterioscler Thromb Vasc Biol 2006; 26: 1405-1412.
    CrossrefPubMedGoogle Scholar
  • 28 Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ. et al. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels. Blood 2005; 106: 4176-4183.
    CrossrefPubMedGoogle Scholar
  • 29 Mannila MN, Eriksson P, Lundman P. et al. Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction. Thromb Haemost 2005; 93: 570-577.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE. et al. A common mutation (G-455--> A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest 1997; 99: 3034-3039.
    CrossrefPubMedGoogle Scholar
  • 31 Drenos F, Miller GJ, Humphries SE. Increase of plasma fibrinogen levels and variability with age in a sample of middle aged healthy men. Ann Hum Genet 2007; 71: 43-53.
    CrossrefPubMedGoogle Scholar
  • 32 Kanters SD, Algra A, van Leeuwen MS. et al. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke 1997; 28: 665-671.
    CrossrefPubMedGoogle Scholar
  • 33 Klein RL, Hunter SJ, Jenkins AJ. et al. Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort. Diabetes Care 2003; 26: 1439-1448.
    CrossrefPubMedGoogle Scholar
  • 34 de Maat MPM, Kastelein JJP, Jukema JW. et al. –455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. Arterioscler Thromb Vasc Biol 1998; 18: 265-271.
    CrossrefPubMedGoogle Scholar
  • 35 Martinez-Vila E, Paramo JA, Beloqui O. et al. Independent association of fibrinogen with carotid intimamedia thickness in asymptomatic subjects. Cerebrovasc Dis 2003; 16: 356-62.
    CrossrefPubMedGoogle Scholar
  • 36 Zannad F, Sass C, Visvikis S. Environmental and genetic determinants of intima-media thickness of the carotid artery. Clin Exp Pharmacol Physiol 2001; 28: 1007-1010.
    CrossrefPubMedGoogle Scholar
  • 37 Sosef MN, Bosch JG, van Oostayen J. et al. Relation of plasma coagulation factor VII and fibrinogen to carotid artery intima-media thickness. Thromb Haemost 1994; 72: 250-254.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Standeven K, Grant P, Carter A. et al. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107: 2326-2330.
    CrossrefPubMedGoogle Scholar
  • 39 Davey Smith G, Harbord R, Milton J. et al. Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies. Arterioscler Thromb Vasc Biol 2005; 25: 2228-2233.
    CrossrefPubMedGoogle Scholar
  • 40 Keavney B, Danesh J, Parish S. et al. Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization'. Int J Epidemiol 2006; 35: 935-943.
    CrossrefPubMedGoogle Scholar
  • 41 Kardys I, Uitterlinden AG, Hofman A. et al. Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: The Rotterdam Study. Thromb Haemost 2007; 97: 288-295.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Lettre G, Lange C, Hirschhorn JN. Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet Epidemiol 2007; 31: 358-362.
    CrossrefPubMedGoogle Scholar
  • 43 Mannila MN, Eriksson P, Ericsson CG. et al. Epistatic and pleiotropic effects of polymorphisms in the fibrinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction. Thromb Haemost 2006; 95: 420-427.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Zdravkovic S, Wienke A, Pedersen NL. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J Intern Med 2002; 252: 247-254.
    CrossrefPubMedGoogle Scholar