Genetic determinants of tissue factor pathway inhibitor plasma levels

Summary

Tissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene.

Keywords

Coagulation - genetic - systematic review - meta-analysis - tissue factor pathway inhibitor

• References

• 1 Wood JP, Ellery PER, Maroney SA. et al. Biology of tissue factor pathway inhibitor. Blood 2014; 123: 2934-2943.
• 2 Huang ZF, Higuchi D, Lasky N. et al. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-951.
• 3 Zakai NA, Lutsey PL, Folsom AR. et al. Total tissue factor pathway inhibitor and venous thrombosis. The Longitudinal Investigation of Thromboembolism Etiology. Thromb Haemost 2010; 104: 207-212.
• 4 Morange PE, Simon C, Alessi MC. et al. Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Circulation 2004; 109: 1343-1348.
• 5 Winckers K, Cate ten H, Hackeng TM. The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 2013; 27: 119-132.
• 6 Almasy L, Soria JM, Souto JC. et al. A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study. Arterioscler Thromb Vasc Biol 2005; 25: 1489-1492.
• 7 Warren DM, Soria JM, Souto JC. et al. Heritability of hemostasis phenotypes and their correlation with type 2 diabetes status in Mexican Americans. Hum Biol 2005; 77: 1-15.
• 8 Bladbjerg EM, de Maat MPM, Christensen K. et al. Genetic influence on thrombotic risk markers in the elderly--a Danish twin study. J Thromb Haemost 2006; 04: 599-607.
• 9 Bladbjerg EM, Madsen JS, Kristensen SR. et al. Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study. J Thromb Haemost 2003; 01: 1208-1214.
• 10 Morange PE, Renucci JF, Charles MA. et al. Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers. Thromb Haemost 2001; 85: 999-1003.
• 11 Broze GJ, Girard TJ. Tissue factor pathway inhibitor: structure-function. Front Biosci (Landmark Ed) 2012; 17: 262-280.
• 12 Summerhayes R. Laboratory Methods for the Assay of Tissue Factor Pathway Inhibitor in Human Plasma. In: Methods in Molecular Biology. Totowa, NJ: Humana Press;; 2013. pp. 289-300.
• 13 Hansen JB, Huseby KR, Huseby NE. et al. Tissue factor pathway inhibitor in complex with low density lipoprotein isolated from human plasma does not possess anticoagulant function in tissue factor-induced coagulation in vitro. Thromb Res 1997; 85: 413-425.
• 14 Sanchez-Solana B, Motwani M, Li DQ. et al. p21-activated Kinase-1 Signaling Regulates Transcription of Tissue Factor and Tissue Factor Pathway Inhibitor. J Biol Chem 2012; 287: 39291-39302.
• 15 Lupu C, Zhu H, Popescu NI. et al. Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 2011; 118: 4463-4471.
• 16 Schuepbach RA, Velez K, Riewald M. Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain. Blood 2011; 117: 6338-6346.
• 17 Ohkura N, Enjyoji K-I, Kamikubo Y-I. et al. A novel degradation pathway of tissue factor pathway inhibitor: incorporation into fibrin clot and degradation by thrombin. Blood 1997; 90: 1883-1892.
• 18 Kleesiek K, Schmidt M, Gotting C. et al. A first mutation in the human tissue factor pathway inhibitor gene encoding [P151L]TFPI. Blood 1998; 92: 3976-3977.
• 19 González-Conejero R, Lozano ML, Corral J. et al. The TFPI 536C-->T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-788.
• 20 Evans G, Langdown J, Brown K. et al. The C536T transition in the tissue factor pathway inhibitor gene is not a common cause of venous thromboembolic disease in the UK population. Thromb Haemost 2000; 83: 511.
• 21 Paciaroni K, Rossi E, Bazzan M. et al. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost 2001; 85: 938-939.
• 22 Junker R, Glahn J, Tidow N. et al. The tissue factor pathway inhibitor C536T mutation is not associated with the risk of stroke in young adults. Thromb Hae-most 2002; 87: 920.
• 23 Moatti D, Seknadji P, Galand C. et al. Polymorphisms of the Tissue Factor Pathway Inhibitor (TFPI) Gene in Patients With Acute Coronary Syndromes and in Healthy Subjects : Impact of the V264M Substitution on Plasma Levels of TFPI. Arterioscler Thromb Vasc Biol 1999; 19: 862-869.
• 24 Amini-Nekoo A, Futers TS, Moia M. et al. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol 2001; 113: 537-543.
• 25 Mues GI, Sarode R. Allele frequencies of tissue factor pathway inhibitor polymorphisms in African-American, Hispanic and Caucasian populations. Thromb Haemost 2002; 88: 875-877.
• 26 Ishikawa J, Okada H, Kato H. et al. Association of Asn221Ser mutation in tissue factor pathway inhibitor- with plasma total tissue factor pathway inhibitor level. Blood Coagul Fibrinolysis 2009; 20: 22-26.
• 27 van der Logt CP, Reitsma PH, Bertina RM. Intron-exon organization of the human gene coding for the lipoprotein-associated coagulation inhibitor: the factor Xa dependent inhibitor of the extrinsic pathway of coagulation. Biochemistry 1991; 30: 1571-1577.
• 28 Moatti D, Haidar B, Fumeron F. et al. A new T-287C polymorphism in the 5’ regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb Haemost 2000; 84: 244-249.
• 29 Miyata T, Sakata T, Kumeda K. et al. C-399T polymorphism in the promoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Hae-most 1998; 80: 345.
• 30 Petit L, Lesnik P, Dachet C. et al. The promoter of human tissue factor pathway inhibitor gene: identification of potential regulatory elements. Thromb Res 1999; 95: 255-262.
• 31 Amini Nekoo A, Iles D. Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter. Thromb Res 2008; 121: 813-819.
• 32 Skretting G, Stavik B, Landvik NE. et al. Functional characterization of polymorphisms in the human TFPI gene. Biochem Biophys Res Commun 2010; 397: 106-111.
• 33 Lincz LF, Adams MJ, Scorgie FE. et al. Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the anti-phospholipid syndrome and carriers of factor V Leiden. Blood Coagul Fibrinolysis 2007; 18: 559-564.
• 34 Sayer MS, Cole VJ, Adams MJ. et al. Polymorphisms in the tissue factor pathway inhibitor gene are not associated with ischaemic stroke. Blood Coagul Fibrinolysis 2007; 18: 703.
• 35 Opstad TB, Pettersen A, Weiss T. et al. Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes. Thrombosis J 2010; 08: 7.
• 36 Little J, Higgins J, Bray M. et al. The HuGENet™ HuGE review handbook, version 1.0. Office of Public Health Genomics Human Genome Epidemiology Network, Centers for Disease Control and Prevention 2006
• 37 Oudot-Mellakh T, Cohen W, Germain M. et al. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project. Br J Haematol 2012; 157: 230-239.
• 38 Antoni G, Morange PE, Luo Y. et al. A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. J Thromb Haemost 2010; 08: 2671-2679.
• 39 Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Software 2010; 36: 1-48.
• 40 Borenstein M, Hedges LV, Higgins JPT. et al. Effect Sizes Based on Means. In: Introduction to Meta-Analysis. Chichester, United Kingdom: John Wiley & Sons, Ltd; 2009. pp. 21-32.
• 41 Gleser L, Olkin I. Stochastically Dependent Effect Sizes. In: Cooper H, Hedges LV, Valentine JC. eds. The Handbook of Research Synthesis and Meta-Analysis. New York:: Russell Sage Foundation;; 2009. pp. 357-376.
• 42 Thakkinstian A, Thompson JR, Minelli C. et al. Choosing between per-geno-type, per-allele, and trend approaches for initial detection of gene–disease association. J Appl Stat 2009; 36: 633-646.
• 43 Moatti D, Meirhaeghe A, Ollivier V. et al. Polymorphisms of the tissue factor pathway inhibitor gene and the risk of restenosis after coronary angioplasty. Blood Coagul Fibrinolysis 2001; 12: 317-323.
• 44 Ameziane N, Seguin C, Borgel D. et al. The –33T-->C polymorphism in intron 7 of the TFPI gene influences the risk of venous thromboembolism, independently of the factor V Leiden and prothrombin mutations. Thromb Haemost 2002; 88: 195-199.
• 45 Sidelmann JJ, Bladbjerg E-M, Gram J. et al. Tissue factor pathway inhibitor relates to fibrin degradation in patients with acute deep venous thrombosis. Blood Coagul Fibrinolysis 2008; 19: 405-409.
• 46 Opstad TB, Eilertsen AL, Høibraaten E. et al. Tissue factor pathway inhibitor polymorphisms in women with and without a history of venous thrombosis and the effects of postmenopausal hormone therapy. Blood Coagul Fibrinolysis 2010; 21: 516-521.
• 47 Opstad TB, Pettersen A-AR, Bratseth V. et al. The Influence of Tissue Factor and Tissue Factor Pathway Inhibitor Polymorphisms on Thrombin Generation in Stable Coronary Artery Disease. Pathophysiol Haemos Thromb 2009; 37: 98-103.
• 48 Segers O, van Oerle R, Cate ten H. et al. Thrombin generation as an intermediate phenotype for venous thrombosis. Thromb Haemost 2010; 103: 114-122.
• 49 Kleesiek K, Schmidt M, Gotting C. et al. The 536C-->T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 1999; 82: 1-5.
• 50 Nordøy A, Bønaa KH, Sandset PM. et al. Relationship between apolipoprotein E polymorphism, postprandial hyperlipemia and hemostatic variables in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2000; 10: 15-23.
• 51 Fedi S, Gensini F, Gori AM. et al. Homocysteine and tissue factor pathway inhibitor levels in patients with Fabry’s disease. J Thromb Haemost 2005; 03: 2117-2119.
• 52 Duckers C, Simioni P, Spiezia L. et al. Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency. Blood 2008; 112: 3615-3623.
• 53 Marchetti M, Castoldi E, Spronk HMH. et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112: 4061-4068.
• 54 Castoldi E, Simioni P, Tormene D. et al. Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost 2010; 08: 294-300.
• 55 Castoldi E, Maurissen LFA, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
• 56 Mulder R, Kate ten MK, Kluin-Nelemans HC. et al. PROS1 Heerlen polymorphism is associated with increased free plasma tissue factor pathway inhibitor levels. Thromb Haemost 2012; 107: 594-596.
• 57 Trégouët D-A, Morange P-E.. Marseille Thrombosis Association Study (MARTHA). Unpublished Data.
• 58 Gagnon F. French-Canadian family study on Factor V Leiden thrombophilia (FVL Family Study). Unpublished Data.
• 59 Kanse SM, Declerck PJ, Ruf W. et al. Factor VII-Activating Protease Promotes the Proteolysis and Inhibition of Tissue Factor Pathway Inhibitor. Arterioscler Thromb Vasc Biol 2012; 32: 427-433.
• 60 Warshawsky I, Herz J, Broze GJ. et al. The low density lipoprotein receptor-related protein can function independently from heparan sulfate proteoglycans in tissue factor pathway inhibitor endocytosis. J Biol Chem 1996; 271: 25873-25879.
• 61 Arnaud E, Moatti D, Emmerich J. et al. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost 1999; 82: 159-160.
• 62 Morgan TM, Xiao L, Lyons P. et al. Investigation of 89 candidate gene variants for effects on all-cause mortality following acute coronary syndrome. BMC Med Genet 2008; 09: 66.
• 63 Prabhakar P, De T, Nagaraja D. et al. The intron 7–33T>C polymorphism in TFPI gene and cerebral venous thrombosis: evidence for a protective role. Thromb Res 2012; 130: 687-689.
• 64 Lee C, Kong M. An Interactive Association of Common Sequence Variants in the Neuropeptide Y Gene With Susceptibility to Ischemic Stroke. Stroke 2007; 38: 2663-2669.
• 65 Pedersen A, Hanson E, Olsson S. et al. TFPI gene variation and ischemic stroke. Thromb Res 2012; 130: 565-567.
• 66 Vincent LM, Tran S, Livaja R. et al. Coagulation factor VA2440G causes east Texas bleeding disorder via TFPI . J Clin Invest 2013; 123: 3777-3787.
• 67 Holroyd EW, Simari RD. Interdependent biological systems, multi-functional molecules: the evolving role of tissue factor pathway inhibitor beyond anti-coagulation. Thromb Res 2010; 125 (Suppl. 01) S57-59.
• 68 Morange PE, Blankenberg S, Alessi MC. et al. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007; 05: 475-482.
• 69 López S, Buil A, Ordoñez J. et al. Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels. Eur J Hum Genet 2008; 16: 1372-1379.
• 70 Nagato LC, de Souza Pinhel MA, de Godoy JMP. et al. Association of ApoE genetic polymorphisms with proximal deep venous thrombosis. J Thromb Thrombolysis 2011; 33: 116-119.
• 71 Bennet AM, Di Angelantonio E, Ye Z. et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. J Am Med Assoc 2007; 298: 1300-1311.
• 72 Hoke M, Kyrle PA, Minar E. et al. Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism. Thromb Haemost 2005; 94: 787-790.
• 73 Novotny WF, Brown SG, Miletich JP. et al. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-393.