Key result
E-selectin S128R polymorphism linked to ~2-fold greater fibrin formation during endotoxemia in healthy men.
Why the study?
The Ser128Arg SNP in the E-selectin gene is overrepresented in patients with atherosclerosis or restenosis, but its effects on inflammation and coagulation in humans are unclear.
Is the Ser128Arg SNP in the E-selectin gene associated with enhanced coagulation during human endotoxemia?
Observational (n=157)
Is the Ser128Arg SNP in the E-selectin gene associated with enhanced coagulation during human endotoxemia?
Effect estimate: 50% to 80% increase in F(1+2); 2-fold increase in D-dimer
p-value: p=< .01 for F(1+2); .01 to .002 for D-dimer
The S128R E-selectin genotype is associated with procoagulant effects in a human endotoxemia model, providing a potential mechanism for its linkage with thrombotic cardiovascular disorders.
S128R carriers show enhanced coagulation in endotoxemia; leaves open its contribution to clinical thrombosis and requires prospective validation.
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 real-time 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.
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Jilma et al. (2004) conducted an observational in Healthy volunteers (human endotoxemia model) (n=157). Ser128Arg (S128R) SNP in the E-selectin gene vs. Non-carriers of the S128R SNP was evaluated on Thrombin generation (prothrombin fragment F(1+2)) and fibrin formation (D-dimer) (50% to 80% increase in F(1+2); 2-fold increase in D-dimer, p=< .01 for F(1+2); .01 to .002 for D-dimer). The S128R SNP in the E-selectin gene enhanced thrombin generation by 50% to 80% (P<0.01) and fibrin formation 2-fold (P=0.01 to 0.002) following lipopolysaccharide infusion in healthy men.
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