Download PDF
Thromb Haemost 2005; 93(03): 570-577
DOI: 10.1160/TH04-10-0698
Cell Signalling and Vessel Remodelling
Schattauer GmbH

Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction

Maria Nastase Mannila
1   Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Per Eriksson
1   Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Pia Lundman
2   Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Ann Samnegård
2   Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Susanna Boquist
2   Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Carl-Göran Ericsson
2   Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Per Tornvall
3   Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Anders Hamsten
1   Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
3   Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Angela Silveira
1   Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
› Author AffiliationsGrant support: This study was supported by grants from the Swedish Medical Research Council (8691), the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Petrus and Augusta Hedlund Foundation, the King Gustaf V and Queen Victoria Foundation, the Foundation for Old Servants, the Professor Nanna Svartz Foundation, the Stockholm County Council and Karolinska Institutet.
Further Information

Publication History

Received 27 October 2004

Accepted after revision 28 February 2004

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of hap-lotypes associated with variation in risk of MI. Of the four haplo-types inferred using the FGA –58G> A and FGG 1299+79T> C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGGFGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.

Keywords

Fibrinogen gene cluster - myocardial infarction - SNPs - haplotypes
 

  • References

  • 1 Danesh J, Collins R, Appleby P. et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998; 279: 1477-82.
    CrossrefPubMedSearch in Google Scholar
  • 2 Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89: 601-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Dalmon J, Laurent M, Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13: 1183-93.
    CrossrefPubMedSearch in Google Scholar
  • 4 Yarnell JW, Sweetnam PM, Rumley A. et al. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
    CrossrefPubMedSearch in Google Scholar
  • 5 Hamsten A, Iselius L, de Faire U. et al. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet 1987; 2: 988-91.
    PubMedSearch in Google Scholar
  • 6 Friedlander Y, Elkana Y, Sinnreich R. et al. Genetic and environmental sources of fibrinogen variability in Israeli families: the Kibbutzim Family Study. Am J Hum Genet 1995; 56: 1194-206.
    PubMedSearch in Google Scholar
  • 7 de Lange M, Snieder H, Ariens RA. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
    CrossrefPubMedSearch in Google Scholar
  • 8 Kant JA, Fornace , Jr. AJ, Saxe D. et al. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci U S A 1985; 82: 2344-8.
    CrossrefPubMedSearch in Google Scholar
  • 9 Otto JM, Grenett HE, Fuller GM. The coordinated regulation of fibrinogen gene transcription by hepatocyte- stimulating factor and dexamethasone. J Cell Biol 1987; 105: 1067-72.
    CrossrefPubMedSearch in Google Scholar
  • 10 Behague I, Poirier O, Nicaud V. et al. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas- Temoins sur l'Infarctus du Myocarde. Circulation 1996; 93: 440-9.
    CrossrefPubMedSearch in Google Scholar
  • 11 de Maat MP, Kastelein JJ, 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 acutephase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol 1998; 18: 265-71.
    CrossrefPubMedSearch in Google Scholar
  • 12 Lim BC, Ariens RA, Carter AM. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-31.
    CrossrefPubMedSearch in Google Scholar
  • 13 Simmonds RE, Hermida J, Rezende SM. et al. Haemostatic genetic risk factors in arterial thrombosis. Thromb Haemost 2001; 86: 374-85.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Eriksson P, Deguchi H, Samnegard A. et al. Human evidence that the cystatin C gene is implicated in focal progression of coronary artery disease. Arterioscler Thromb Vasc Biol 2004; 24: 551-7.
    CrossrefPubMedSearch in Google Scholar
  • 15 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
    CrossrefPubMedSearch in Google Scholar
  • 16 Carlson K. Lipoprotein fractionation. J Clin Pathol Suppl (Assoc Clin Pathol) 1973; 5: 32-7.
    PubMedSearch in Google Scholar
  • 17 Fatah K, Silveira A, Tornvall P. et al. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76: 535-40.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations. Hum Genet 2001; 109: 121-4.
    CrossrefPubMedSearch in Google Scholar
  • 19 Skoglund-Andersson C, Tang R, Bond MG. et al. LDL particle size distribution is associated with carotid intima-media thickness in healthy 50-year-old men. Arterioscler Thromb Vasc Biol 1999; 19: 2422-30.
    CrossrefPubMedSearch in Google Scholar
  • 20 van't Hooft FM, von Bahr SJ, Silveira A. et al. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol 1999; 19: 3063-70.
    CrossrefPubMedSearch in Google Scholar
  • 21 Ott JS. Analysis of Human Genetic Linkage. Rev. edition. Johns Hopkins University Press: Baltimore, MD; 1991
    Search in Google Scholar
  • 22 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-89.
    CrossrefPubMedSearch in Google Scholar
  • 23 Li N, Stephens M. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 2003; 165: 2213-33.
    PubMedSearch in Google Scholar
  • 24 Fellowes AP, Brennan SO, George PM. Identification and characterization of five new fibrinogen gene polymorphisms. Ann N Y Acad Sci 2001; 936: 536-41.
    PubMedSearch in Google Scholar
  • 25 Menegatti M, Asselta R, Duga S. et al. Identification of four novel polymorphisms in the Aalpha and gamma fibrinogen genes and analysis of association with plasma levels of the protein. Thromb Res 2001; 103: 299-307.
    CrossrefPubMedSearch in Google Scholar
  • 26 Baumann RE, Henschen AH. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at positions A alpha 312 and B beta 448. Blood 1993; 82: 2117-24.
    PubMedSearch in Google Scholar
  • 27 Mannila MN, Silveira A, Hawe E. et al. Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors. The HIFMECH Study. Thromb Haemost 2004; 92: 1240-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Daly MJ, Rioux JD, Schaffner SF. et al. High-resolution haplotype structure in the human genome. Nat Genet 2001; 29: 229-32.
    CrossrefPubMedSearch in Google Scholar
  • 29 Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003; 33 Suppl 228-37.
    CrossrefPubMedSearch in Google Scholar
  • 30 Zhang K, Qin ZS, Liu JS. et al. Haplotype block partitioning and tag SNP selection using genotype data and their applications to association studies. Genome Res 2004; 14: 908-16.
    CrossrefPubMedSearch in Google Scholar
  • 31 Baumann RE, Henschen AH. Linkage disequilibrium relationships among four polymorphisms within the human fibrinogen gene cluster. Hum Genet 1994; 94: 165-70.
    PubMedSearch in Google Scholar
  • 32 Yu S, Sher B, Kudryk B. et al. Intracellular assembly of human fibrinogen. J Biol Chem 1983; 258: 13407-10.
    PubMedSearch in Google Scholar
  • 33 Doggen CJ, Bertina RM, Cats VM. et al. Fibrinogen polymorphisms are not associated with the risk of myocardial infarction. Br J Haematol 2000; 110: 935-8.
    CrossrefPubMedSearch in Google Scholar
  • 34 Leander K, Wiman B, Hallqvist J. et al. The G-455A polymorphism of the fibrinogen Bbeta-gene relates to plasma fibrinogen in male cases, but does not interact with environmental factors in causing myocardial infarction in either men or women. J Intern Med 2002; 252: 332-41.
    CrossrefPubMedSearch in Google Scholar
  • 35 Humphries SE, Cook M, Dubowitz M. et al. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; 1: 1452-5.
    PubMedSearch in Google Scholar
  • 36 Youngman L, Keavney B, Palmer A. et al. Plasma fibrinogen and fibrinogen genotypes in 4685 cases of myocardial infarction and 6002 controls: test of causality by ‘Mendelian randomisation’. Circulation 2000; 102: 31-2.
    CrossrefPubMedSearch in Google Scholar
  • 37 Keavney B, Palmer A, Parish S. et al. Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk. Int J Epidemiol 2004; 33: 1002-13.
    CrossrefPubMedSearch in Google Scholar
  • 38 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-63.
    CrossrefPubMedSearch in Google Scholar
  • 39 Ma J, Hennekens CH, Ridker PM. et al. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians' Health Study. J Am Coll Cardiol 1999; 33: 1347-52.
    CrossrefPubMedSearch in Google Scholar
  • 40 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.
    CrossrefPubMedSearch in Google Scholar
  • 41 Lovely RS, Falls LA, Al-Mondhiry HA. et al. Association of gammaA/gamma' fibrinogen levels and coronary artery disease. Thromb Haemost 2002; 88: 26-31.
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Collet JP, Nagaswami C, Farrell DH. et al. Influence of gamma' fibrinogen splice variant on fibrin physical properties and fibrinolysis rate. Arterioscler Thromb Vasc Biol 2004; 24: 382-6.
    CrossrefPubMedSearch in Google Scholar
  • 43 Friedlander Y, Kark JD, Sinnreich R. et al. Combined segregation and linkage analysis of fibrinogen variability in Israeli families: evidence for two quantitative- trait loci, one of which is linked to a functional variant (-58G > A) in the promoter of the alpha-fibrinogen gene. Ann Hum Genet 2003; 67: 228-41.
    CrossrefPubMedSearch in Google Scholar
  • 44 Guo M, Sahni SK, Sahni A. et al. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb Haemost 2004; 92: 858-66.
    Thieme ConnectPubMedSearch in Google Scholar
  • 45 Johnson GC, Esposito L, Barratt BJ. et al. Haplotype tagging for the identification of common disease genes. Nat Genet 2001; 29: 233-7.
    CrossrefPubMedSearch in Google Scholar
  • 46 Risch NJ. Searching for genetic determinants in the new millennium. Nature 2000; 405: 847-56.
    CrossrefPubMedSearch in Google Scholar
  • 47 Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests: what do we gain?. Eur J Hum Genet 2001; 9: 291-300.
    CrossrefPubMedSearch in Google Scholar
  • 48 Thomas A, Lamlum H, Humphries S. et al. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), C/T-148 (HindIII/AluI), T/G+1689 (AvaII), and BclI (beta-fibrinogen) and TaqI (alpha-fibrinogen), and their detection by PCR. Hum Mutat 1994; 3: 79-81.
    CrossrefPubMedSearch in Google Scholar