The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia

Abstract

The single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient groups with atherosclerosis or restenosis. We hypothesized and tested whether it may affect cytokine-induced levels of soluble (s) E-selectin, or be associated with proinflammatory or procoagulant properties in a well-standardized inflammation model. Healthy male volunteers (n ‫؍‬ 157) received a lipopolysaccharide (LPS) infusion and were genotyped for the S128R SNP, and outcome parameters were measured by enzyme immunoassays and realtime polymerase chain reaction (RT-PCR, Taqman). The S128R SNP had no pronounced effects on basal or inducible sE-selectin levels, or levels of tumor necrosis factor or interleukin-6. However, carriers of the S128R SNP had 20% higher monocyte counts at 24 hours after LPS infusion. Importantly, the S128R allele enhanced thrombin generation by 50% to 80%, as measured by prothrombin fragment F 1؉2 (P < .01), and hence fibrin formation (D-dimer) 2-fold (P ‫؍‬ .01 to P ‫؍‬ .002). However, tissue factor (TF) mRNA levels were not affected. The S128R E-selectin genotype is associated with procoagulant effects in a human model of endotoxin-induced, TF-triggered coagulation. This could contribute to its linkage with various thrombotic cardiovascular disorders. (Blood. 2005;105:2380-2383)

Homozygosity in the Single Nucleotide Polymorphism Ser128Arg in the E-Selectin Gene Associated With Recurrent Venous Thromboembolism

“…31 This is not surprising and is owing to the inclusion criteria of the study population. However, the frequency of the S128R mutation in our cohort of patients with VTE was not different from healthy young volunteers 15 or other patient groups 14,22 in Austria. This provides indirect evidence that the S128R allele may not be associated with an increased risk for the first VTE episode.…”

“…A power calculation indicates that we had 80% power (␣=.05) to detect a 53% higher rate of VTE in heterozygous individuals vs patients with the frequent allele at 18 months. Of interest, heterozygous carriers of the Ser128Arg allele had markedly enhanced thrombin generation 15 in our human model where tissue factor-mediated coagulation [27][28][29] is induced by endotoxin infusion. In the present study, D dimer levels were only insignificantly (20%) higher in carriers of the mutant allele.…”

E-Selectin Genetic Variation as a Susceptibility Factor for Ischemic Stroke

“…Finally, the E-selectin S128R genotype is associated with procoagulant effects in a human model of endotoxin-induced tissue-factor-triggered coagulation. This could contribute to its linkage with various thrombotic cardiovascular disorders [32]. The participants in our study were from Kurd, Turk and Pars ethnic backgrounds.…”

Role of S128R polymorphism of E‐selectin in colon metastasis formation

“…[28][29][30] Our hypothesis was that a functional polymorphism (associated with a variation in the structure and ligand affinity of the molecule) affecting E-selectin could influence cancer cell biological behavior and colon cancer risk. The Ser128Arg polymorphism in the E-selectin gene has been associated with a higher risk of severe atherosclerosis, 15 myocardial infarction, 31 ischemic cerebrovascular disease, 32 enhanced coagulation and systemic lupus erythematosus 20,33,34 ; pathologies where increased leukocyte-endothelial cells interaction are observed. From a biological point of view, this specific polymorphism has been demonstrated to exert a significant effect on ligand recognition and binding, as cell transfectants expressing the a561c E-selectin allele better support interactions with leukocytes under shear flow conditions.…”