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

Summary

An intricate interplay between the genes encoding fibrinogen gamma (FGG), alpha (FGA) and beta (FGB), coagulation factor XIII (F13A1) and interleukin6 (IL6) and environmental factors is likely to influence plasma fibrinogen concentration, fibrin clot structure and risk of myocardial infarction (MI). In the present study, the potential contribution of SNPs harboured in the fibrinogen, IL6 and F13A1 genes to these biochemical and clinical phenotypes was examined. A database and biobank based on 387 survivors ofa first MI and population-based controls were used. Sixty controls were selected according to FGG 9340T>C [rs1049636] genotype for studies on fibrin clot structure using the liquid permeation method. The multifactor dimensionality reduction method was used for interaction analyses. We here report that the FGA 2224G>A [rs2070011] SNP (9.2%), plasma fibrinogen concentration (13.1%) and age (8.1%) appeared as independent determinants of fibrin gel porosity. The FGA 2224G>A SNP modulated the relation between plasma fibrinogen concentration and fibrin clot porosity. The FGG-FGA*4 haplotype, composed of the minor FGG 9340C and FGA 2224A alleles, had similar effects, supporting its reported protective role in relation to MI. Significant epistasis on plasma fibrinogen concentration was detected between the FGA 2224G>A and F13A1 Val34Leu [rs5985] SNPs (p<0.001).The FGG 9340T>C and FGB 1038G>A [rs1800791] SNPs appeared to interact on MI risk, explaining the association of FGG-FGB haplotypes with MI in the absence of effects of individual SNPs. Thus, epistatic and pleiotropic effects of polymorphisms contribute to the variation in plasma fibrinogen concentration, fibrin clot structure and risk of MI.

Keywords

Epistasis - fibrinogen clot structure - myocardial infarction - plasma fibrinogen concentration - pleiotropy

• 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. JAMA 2005; 294: 1799-809.
• 2 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: 570-7.
• 3 Blombäck B, Carlsson K, Fatah K. et al. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994; 75: 521-38.
• 4 Standeven KF, Grant PJ, Carter AM. et al. Functional analysis of the fibrinogen Aα Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107: 2326-30.
• 5 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.
• 6 Collet JP, Soria J, Mirshahi M. et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82: 2462-9.
• 7 Fatah K, Hamsten A, Blombäck B. et al. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992; 68: 130-5.
• 8 Carter AM, Catto AJ, Grant PJ. Association of the a-fibrinogen Thr312Ala polymorphism with poststroke mortality in subjects with atrial fibrillation. Circulation 1999; 99: 2423-6.
• 9 Kohler HP, Stickland MH, Ossei-Gerning N. et al. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost 1998; 79: 8-13.
• 10 Warner D, Mansfield MW, Grant PJ. Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography. Thromb Haemost 2001; 85: 408-11.
• 11 Dunn EJ, Ariens RA, de Lange M. et al. Genetics of fibrin clot structure:a twin study. Blood 2004; 103: 1735-40.
• 12 Hamsten A, Iselius L, de Faire U. et al. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet 1987; 02: 988-91.
• 13 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.
• 14 de Lange M, Snieder H, Ariens RA. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
• 15 Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ. et al. Genetic variation in the fibrinogen gamma gene increases the risk of deep venous thrombosis by reducing plasma fibrinogen γ’ levels. Blood 2005; 106: 4176-83.
• 16 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.
• 17 Soria JM, Almasy L, Souto JC. et al. A genome search for genetic determinants that influence plasma fibrinogen levels. Arterioscler Thromb Vasc Biol 2005; 25: 1287-92.
• 18 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.
• 19 Luc G, Bard JM, Juhan-Vague I. et al. C-Reactive Protein, Interleukin-6, and Fibrinogen as Predictors of Coronary Heart Disease. The PRIME Study. Arterioscler Thromb Vasc Biol 2003; 23: 1255-61.
• 20 Fishman D, Faulds G, Jeffery R. et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369-76.
• 21 Georges JL, Loukaci V, Poirier O. et al. Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-Temoin de l’Infarctus du Myocarde. J Mol Med 2001; 79: 300-5.
• 22 Lieb W, Pavlik R, Erdmann J. et al. No association of interleukin-6 gene polymorphism (-174 G/C) with myocardial infarction or traditional cardiovascular risk factors. Int J Cardiol 2004; 97: 205-12.
• 23 Cooper AV, Standeven KF, Ariens RA. Fibrinogen gamma chain splice variant γ’ alters fibrin formation and structure. Blood 2003; 102: 535-40.
• 24 Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting genegene and gene-environment interactions. Bioinformatics 2003; 19: 376-82.
• 25 Samnegård A, Silveira A, Lundman P. et al. Serum matrix metalloproteinase-3 concentration is influenced by MMP-3 -1612 5A/6A promoter genotype and associated with myocardial infarction. J Intern Med 2005; 258: 411-9.
• 26 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
• 27 Carlson K. Lipoprotein fractionation. J Clin Pathol Suppl 1973; 05: 32-7.
• 28 Lewis PO, Zaykin D. Genetic Data Analysis, Version 1.0 (d16c). 1999
• 29 Raymond M, Rousset F. An exact test for population differentiation. Evolution 1995; 49: 1280-3.
• 30 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-89.
• 31 Cheverud JM, Routman EJ. Epistasis and its contribution to genetic variance components. Genetics 1995; 139: 1455-61.
• 32 Pastinen T, Hudson TJ. Cis-acting regulatory variation in the human genome. Science 2004; 306: 647-50.
• 33 Carter AM, Sachchithananthan M, Stasinopoulos S. et al. Prothrombin G20210A is a bifunctional gene polymorphism. Thromb Haemost 2002; 87: 846-53.
• 34 Gehring NH, Frede U, Neu-Yilik G. et al. Increased efficiency of mRNA 3’ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 2001; 28: 389-92.
• 35 Ober C, Aldrich CL, Chervoneva I. et al. Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet 2003; 72: 1425-35.
• 36 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 α-fibrinogen gene. Ann Hum Genet 2003; 67: 228-41.
• 37 Marin F, Corral J, Roldan V. et al. Factor XIII Val34Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation. J Mol Cell Cardiol 2004; 37: 699-704.
• 38 Dardik R, Loscalzo J, Eskaraev R. et al. Molecular mechanisms underlying the proangiogenic effect of factor XIII. Arterioscler Thromb Vasc Biol 2005; 25: 526-32.
• 39 Wartiovaara U, Mikkola H, Szoke G. et al. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost 2000; 84: 595-600.
• 40 Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275: 18138-44.
• 41 Ritchie MD, Hahn LW, Roodi N. et al. Multifactordimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69: 138-47.
• 42 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.
• 43 Jörneskog G, Hansson LO, Wallen NH. et al. Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion. J Thromb Haemost 2003; 01: 1195-201.
• 44 Nickerson D. Seattle SNP:NHLBI Program for Genomic Applications, UW-FHCRC. Seattle, WA: http://pga.gs.washington.edu 2003