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

Cihan Ay; Lea V. Jungbauer; Alexandra Kaider; Silvia Koder; Simon Panzer; Ingrid Pabinger; Christine Mannhalter

doi:10.1160/TH07-11-0672

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(05): 899-904
DOI: 10.1160/TH07-11-0672

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Cihan Ay^*

¹Division of Haematology and Haemostaseology, Department of Internal Medicine I

,

Lea V. Jungbauer^*

²Clinical Institute of Medical and Chemical Laboratory Diagnostics

,

Alexandra Kaider

³Core Unit for Medical Statistics and Informatics, Section of Clinical Biometrics

,

Silvia Koder

¹Division of Haematology and Haemostaseology, Department of Internal Medicine I

,

Simon Panzer

⁴Clinic for Blood Group Serology; all Medical University Vienna, Vienna, Austria

,

Ingrid Pabinger

¹Division of Haematology and Haemostaseology, Department of Internal Medicine I

,

Christine Mannhalter

²Clinical Institute of Medical and Chemical Laboratory Diagnostics

› Author Affiliations

Abstract

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

Full Text

References

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