Homozygosity in the single nucleotide polymorphism Ser128Arg in the E-selectin gene associated with recurrent venous thromboembolism.
BACKGROUND
The single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient populations with atherosclerosis or restenosis. As this SNP enhances tissue factor-triggered coagulation in humans during systemic inflammation, we hypothesized that it may also predispose for the development of recurrent venous thromboembolism (VTE).


METHODS
A total of 585 patients were prospectively observed after first VTE for recurrent, objectively documented, symptomatic VTE. Patients with secondary VTE, homozygous factor V Leiden, natural inhibitor deficiencies, lupus anticoagulant, or long-term anticoagulation therapy were excluded. The S128R SNP was genotyped by mutagenically separated polymerase chain reaction.


RESULTS
A total of 102 patients (17%) were heterozygous, and 11 were homozygous (2%) for the Ser128Arg mutation. Ninety patients (15%) had recurrent VTE during follow-up. Homozygosity for the Ser128Arg SNP increased the cumulative likelihood, particularly for early recurrent VTE (log rank test, P<.05) and was an independent predictor of recurrent VTE (hazard ratio [HR], 4.1; 95% confidence interval [CI], 1.5-11.4) in a multivariate Cox regression model. In contrast, heterozygosity for the polymorphism was associated with an unaltered HR (HR, 1.1; 95% CI, 0.6-1.9) for recurrent VTE.


CONCLUSIONS
Homozygosity for the S128R E-selectin allele appears to increase the risk for recurrent VTE several fold. If these findings are confirmed, this may represent a novel risk factor for recurrent VTE. These results also expand our knowledge on the association of this SNP with thrombotic disorders.
Jilma
Bernd
B
Department of Clinical Pharmacology, and Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Bernd.Jilma@meduniwien.ac.at
Kovar
Florian M
FM
Hron
Gregor
G
Endler
Georg
G
Marsik
Claudia L
CL
Eichinger
Sabine
S
Kyrle
Paul A
PA
D000328:Adult; D001120:Arginine; D019040:E-Selectin / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012694:Serine; D013923:Thromboembolism / Q000235:genetics*; D020246:Venous Thrombosis / Q000235:genetics*
D019040:E-Selectin; D012694:Serine; D001120:Arginine