The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia.
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.
Jilma
Bernd
B
Department of Clinical Pharmacology, Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Wien, Austria. bernd.jilma@meduniwien.ac.at
Marsik
Claudia
C
Kovar
Florian
F
Wagner
Oswald F
OF
Jilma-Stohlawetz
Petra
P
Endler
Georg
G
D019943:Amino Acid Substitution; D001777:Blood Coagulation / Q000235:genetics*; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000097:blood / Q000235:genetics*; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000032:analysis; D013927:Thrombosis / Q000097:blood / Q000235:genetics
D016207:Cytokines; D019040:E-Selectin; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; C036309:fibrin fragment D; D013917:Thrombin