Synergistic association between hypercholesterolemia and the C46T factor XII polymorphism for developing premature myocardial infarction

Summary

Factor XII (FXII) plays a key role in both coagulation and fibrinolysis, thus its role in thrombotic processes is uncertain. Both genetic and environmental factors determine FXII plasma levels. A common C46T polymorphism in the Kozak region of F12 gene disturbs the translation of the protein leading to a significant reduction of FXII levels although its clinical significance is conflictive. We studied the F12 C46T polymorphism in 281 patients who had suffered from an acute myocardial infarction (MI) before 45-year-old and 550 control subjects from the same area. Serum levels of cholesterol, HDL, LDL, triglycerides and C reactive protein (CRP) were assayed in the MI group. The 46T allele slightly increased the risk to suffer from premature MI (OR:1.64; 95%CI: 1.14–2.37; p= 0.008). Moreover, patients carrying the 46T allele showed increased levels of CRP (p= 0.002). Interestingly, we found that the simultaneous presence of the 46T allele and hypercholesterolemia increases the risk to develop premature MI 2.26 times. The F12 C46T polymorphism, associated with a reduction of plasma FXII levels, seems to play a deleterious effect, predisposing the development of premature MI, especially in hypercholesterolemic patients. This effect could be associated with an increased pro-inflammatory state, as the 46T allele associates with high levels of CRP.

Keywords

Factor XII - genetic polymorphism - premature myocardial infarction - Hypercholesterolemia

• References

• 1 Colman RW, Schamier AH. Contact System: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-43.
• 2 Bradford HN, Pixley RA, Colman RW. Human Factor XII Binding to the Glycoprotein Ib-IX-V Complex Inhibits Thrombin-induced Platelet Aggregation. J Biol Chem 2000; 275: 22756-63.
• 3 Colman RW. Biological activities of the contact factors in vivo. Potentiation of hypotension, inflammation, and fibrinolysis, and inhibition of cell adhesion, angiogenesis and thrombosis. Thromb Haemost 1999; 82: 1568-77.
• 4 Miller GJ, Esnouf MP, Burgss AI. et al Risk of coronary heart disease and activation of factor XII in middle-aged men. Arterioscl Thromb Vasc Biol 1997; 17: 2103-6.
• 5 Kohler HP, Futers TS, Grant PJ. FXII (46C→T) polymorphism and in vivo generation of FXII activity. Thromb Haemost 1999; 81: 745-7.
• 6 Zito F, Drummond F, Bujac S. et al Epidemiological and genetic association of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men. Circulation 2000; 102: 2058-62.
• 7 Cooper JA, Miller GJ, Bauer KA. et al Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816-22.
• 8 Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 1986; 44: 283-92.
• 9 Kanaji T, Okamura T, Osaki K. et al A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII-gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-14.
• 10 Halbmayer WM, Mannhalter C, Feichtinger C. et al The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism. Thromb Haemost 1992; 68: 285-90.
• 11 Halbmayer WM, Haushofer A, Radek J. et al Prevalence of factor XII (Hageman factor) deficiency amon 426 patients with coronary heart disease awaiting cardiac surgery. Coron Artery Dis 1994; 5: 451-4.
• 12 Kohler HP, Carter AM, Stickland MH. et al Levels of activated XII in survivors of myocardial infarction. Association with circulating risk factors and extent of coronary artery disease. Thromb Haemost 1998; 79: 14-8.
• 13 Zito F, Lowe G, Rumley A. et al Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study. Atherosclerosis 2002; 165: 153-8.
• 14 Oguchi S, Ito D, Murata M. et al Genotype distribution of the 46C/T polymorphism of coagulation factor XII in the Japanese population: absence of its association with ischaemic heart disease. Thromb Haemost 2000; 83: 178-9.
• 15 Orth M, Westphal S, Dierkers J. et al Rapid Factor XII (46C→T) genotipying by fluorescence resonance energy transfer in patients with coronary artery disease or thrombophilia. Clin Chem 2001; 47: 1117-9.
• 16 Endler G, Mannhalter C, Sunder-Plassmann H. et al Homozygosity for the C→T polymorphism at nucleotide 46 in the 5’ untranslated region of the factor XII gene protects from development of acute coronary syndromes. Br J Hematol 2001; 115: 1007-9.
• 17 Soria JM, Almasy L, Souto JC. et al A quantitativetrait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet 2002; 70: 567-74.
• 18 Tirado I, Soria JM, Mateo J. et al Association after linkage analysis indicates that homozygosity for the 46C→T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis. Thromb Haemost 2004; 91: 899-904.
• 19 Santamaría A, Mateo J, Tirado I. et al Homozygosity of the T allele of the 46C→T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population. Stroke 2004; 35: 1795-9.
• 20 Santamaría A, Martínez-Rubio A, Mateo J. et al Homozygosity of the T allele of the 46C→T polymorphism in the F12 gene is a risk factor for acute coronary heart disease in the Spanish population. Haematologica 2004; 89: 878-9.
• 21 Bertina RM, Poort SR, Vos HL. et al The 46C/T polymorphism in the factor XII gene (F12) and the risk of venous trombosis. J Thromb Haemost 2005; 3: 597-9.
• 22 Zimmerman FH, Cameron A, Fisher LD. et al Myocardial infarction in young adults: angiographic characterization, risk factors and prognosis (Coronary Artery Surgery Study Registry). J Am Coll Cardiol 1995; 26: 654-61.
• 23 Ardissino D, Mannucci PM, Merlín PA. et al Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 1999; 94: 46-51.
• 24 Gonzalez-Conejero R, Corral J, Roldan V. et al A common polymorphism in the annexin V Kozak sequence (-1C>T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients. Blood 2002; 100: 2081-6.
• 25 Corral J, Iniesta JA, Gonzalez-Conejero R. et al Detection of factor V Leiden from a drop of blood by PCRSSCP. Thromb Haemost 1996; 76: 735-7.
• 26 Grundt H, Nilsen DWT, WT Hetland. et al Activated factor 12 (FXIIa) predicts recurrent coronary events after an acute myocardial infarction. Am Heart J 2004; 147: 260-6.
• 27 Bouma BN, Meijers JCM. Fibrinolysis and the contact system: a role for factor XI in the down-regulation of fibrinolysis. Thromb Haemost 1999; 82: 243-50.
• 28 Hack CE. The role of factor XII in contact system activation. Blood 1998; 92: 703-4.
• 29 Braat EAM, Dooijewaard G, Rijken DC. Fibrinolytic properties of activated FXII. Eur J Biochem 1999; 263: 904-11.
• 30 Schousboe I, Feddersen K, Rojkajaer R. Factor XIIa in a kinetically favourable plasminogen activator. Thromb Haemost 1999; 82: 1041-6.
• 31 Fuster V, A Fayad Z, Badimon JJ. Acute coronary syndromes: biology. Lancet 1999; 353 (Suppl. 02) 5-9.
• 32 Ridker PM, Vaughan DE, Stampfer MJ. et al Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 33 Thompson SG, Kienast J, Pyke SDM. et al Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Eng J Med 1995; 332: 635-41.
• 34 Tracy RP. Thrombin, inflammation, and cardiovascular disease. Chest 2003; 124: 49S-57S.
• 35 Dick J, McClaren M, Ford R. The effect of atorvastatin on activated factor XII, fibrinogen and lipid profile. Haemostasis 2000; 30: 30-7.