P-selectin gene haplotypes modulate soluble P-selectin concentrations and contribute to the risk of venous thromboembolism

Summary

The cell adhesion molecule P-selectin mediates the interaction of activated platelets or endothelial cells with leukocytes. In arterial and venous thromboembolism (VTE) increased soluble P-selectin (sP-selectin) concentrations have been found, and associations of P-selectin genotypes with thrombotic disease have been proposed. We assessed the effect of four single nucleotide polymorphisms (SNPs) [one in the promoter region (c.–2123C>G) and three (S290N, c.1087G>A; D562N, c.1902G>A; T715P, c.2363A>C) in the coding region] and the calculated haplotypes in the P-selectin gene (SELP) on sP-selectin concentrations and VTE risk. The analysis was carried out in 116 high-risk patients with a history of objectively confirmed recurrent VTE and 129 age- and sex-matched healthy individuals. Haplotypes were generated using computer-assisted haplotype reconstruction with Phase 2.1. sP-selectin (μg/l) was measured by ELISA. Frequencies of all four individual SNPs were not statistically significantly different between patients and controls. Tenhaplotypes were obtained for the control population, and nine for the patient group. The most frequent haplotype among controls was CGGA (major allele at all positions) (27.8%; frequency in patients 19.0%), which was used as reference for statistical analyses. Among patients GGAA was most frequent (23.3%; frequency in controls 17.5%). Haplotypes were significantly associated with sP-selectin concentrations in patients and in controls (p<0.001 and p=0.011). Compared to CGGA some but not all haplotypes conferred an increased risk for VTE with odds ratios (ORs) between 5.4 (95% CI: 2.5–12.2) for CAGA, 3.3 (1.2–9.2) for CGAC, and 2.4 (1.3–4.7) for GGAA. All ORs remained statistically significant after adjustment for the factor V Leiden mutation, located in close proximity to SELP on chromosome 1, as well as all other established risk factors for VTE. In conclusion, SELP haplotypes modulate plasma concentrations of sP-selectin and affect the risk of recurrent VTE.

Keywords

P-selectin - haplotypes - deep venous thrombosis - pulmonary embolism - venous thromboembolism

^* These authors contributed equally.

• References

• 1 Palabrica T, Lobb R, Furie BC. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-851.
• 2 Celi A, Pellegrini G, Lorenzet R. et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 1994; 91: 8767-8771.
• 3 Andre P, Hartwell D, Hrachovinova I. et al. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci USA 2000; 97: 13835-13840.
• 4 Falati S, Liu Q, Gross P. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-1598.
• 5 Myers DD, Hawley AE, Farris DM. et al. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075-1089.
• 6 Ikeda H, Takajo Y, Ichiki K. et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92: 1693-1696.
• 7 Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001; 103: 491-495.
• 8 Blann AD, Dobrotova M, Kubisz P. et al. von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. Thromb Haemost 1995; 74: 626-630.
• 9 Nadar SK, Lip GY, Blann AD. Platelet morphology, soluble P selectin and platelet P-selectin in acute ischaemic stroke. The West Birmingham Stroke Project. Thromb Haemost 2004; 92: 1342-1348.
• 10 Rectenwald JE, Myers DD, Jr. Hawley AE. et al. D-dimer, P-selectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005; 94: 1312-1317.
• 11 Blann AD, Noteboom WM, Rosendaal FR. Increased soluble P-selectin levels following deep venous thrombosis: cause or effect?. Br J Haematol 2000; 108: 191-193.
• 12 Ay C, Jungbauer LV, Sailer T. et al. High concentrations of soluble P-selectin are associated with risk of venous thromboembolism and the P-selectin Thr715 variant. Clin Chem 2007; 53: 1235-1243.
• 13 Bugert P, Pabinger I, Stamer K. et al. The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154. Thromb Haemost 2007; 97: 573-580.
• 14 Kyrle PA, Hron G, Eichinger S. et al. Circulating P-selectin and the risk of recurrent venous thromboembolism. Thromb Haemost 2007; 97: 880-883.
• 15 Herrmann SM, Ricard S, Nicaud V. et al. The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction. Hum Mol Genet 1998; 7: 1277-1284.
• 16 Barbaux SC, Blankenberg S, Rupprecht HJ. et al. Association between P-selectin gene polymorphisms and soluble P-selectin levels and their relation to coronary artery disease. Arterioscler Thromb Vasc Biol 2001; 21: 1668-1673.
• 17 Carter AM, Anagnostopoulou K, Mansfield MW. et al. Soluble P-selectin levels, P-selectin polymorphisms and cardiovascular disease. J Thromb Haemost 2003; 1: 1718-1723.
• 18 Tregouet DA, Barbaux S, Escolano S. et al. Specific haplotypes of the P-selectin gene are associated with myocardial infarction. Hum Mol Genet 2002; 11: 2015-2023.
• 19 Zalewski G, Ciccarone E, Di Castelnuovo A. et al. P-selectin gene genotypes or haplotypes and cardiovascular complications in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2006; 16: 418-425.
• 20 Volcik KA, Ballantyne CM, Coresh J. et al. P-selectin Thr715Pro polymorphism predicts P-selectin levels but not risk of incident coronary heart disease or ischemic stroke in a cohort of 14595 participants: the Atherosclerosis Risk in Communities Study. Atherosclerosis 2006; 186: 74-79.
• 21 Ferrari J, Rieger S, Endler G. et al. The Thr715Pro polymorphism of the P-selectin gene is not associated with ischemic stroke risk. Stroke 2007; 38: 395-397.
• 22 Volcik KA, Ballantyne CM, Coresh J. et al. Specific P-selectin and P-selectin glycoprotein ligand-1 genotypes/haplotypes are associated with risk of incident CHD and ischemic stroke: The Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 2007; 195: e76-82.
• 23 Ruchaud-Sparagano MH, Malaud E, Gayet O. et al. Mapping the epitope of a functional P-selectin monoclonal antibody (LYP20) to a short complement-like repeat (SCR4) domain: use of human-mouse chimaera and homologue-replacement mutagenesis. Biochem J 1998; 332: 309-314.
• 24 Ay C, Tengler T, Vormittag R. et al. Venous thromboembolism– a manifestation of the metabolic syndrome. Haematologica 2007; 92: 374-380.
• 25 Ay C, Bencur P, Vormittag R. et al. The angiotensin-converting enzyme insertion/deletion polymorphism and serum levels of angiotensin-converting enzyme in venous thromboembolism. Data from a case control study. Thromb Haemost 2007; 98: 777-782.
• 26 Zaykin DV, Westfall PH, Young SS. et al. Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 2002; 53: 79-91.
• 27 Heinze G, Schemper M. A solution to the problem of separation in logistic regression. Stat Med 2002; 21: 2409-2419.
• 28 de Willige SU, de Visser MC, Vos HL. et al. Selectin haplotypes and the risk of venous thrombosis; influence of linkage disequilibrium with the Factor V Leiden mutation. J Thromb Haemost. 2007