Submitted April 7, 2006
Accepted April 10, 2006
The thrombospondin-1 N700S polymorphism is associated with
early myocardial infarction without altering von
Willebrand Factor multimer size
Jeffrey I Zwicker*, Flora Pevandi, Roberta Palla, Rossana Lombardi, Maria Teresa Canciani, Andrea Cairo, Diego Ardissino, Luisa Bernardinelli, Kenneth A Bauer, Jack Lawler, and P.M. Mannucci
Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
A. Bianchi Bonomi Hemophilia and Thrombois Center, University of Milan
Maggiore Hospital, University of Parma
Medical Research Council Biostatistics Unit, Cambridge (UK)
Beth Israel Deaconess Medical Center
* Corresponding author; email: jzwicker{at}bidmc.harvard.edu.
The N700S polymorphism of thrombospondin-1 (TSP-1) has
been identified as a potential genetic risk factor for
myocardial infarction (MI). In a large case-control
study of 1425 individuals who survived a myocardial
infarction prior to age 45, the N700S polymorphism was a
significant risk factor for myocardial infarction in
both homozygous (OR 1.9, 95% CI 1.1-3.3, P=0.01) and
heterozygous carriers of the S700 allele (OR 1.4, 95% CI
1.1-3.3, P=0.01) . TSP-1 has been shown to reduce von
Willebrand Factor (VWF) multimer size and the domain
responsible for VWF-reducing activity has been localized
to the calcium-binding C-terminal sequence. As the N700S
polymorphism was previously shown to alter the function
of this domain, we investigated whether the altered VWF-
reducing activity of TSP-1 underlies the observed
prothrombotic phenotype. The TSP-1 N700S polymorphism
did not influence VWF multimer size in patients
homozygous for either allele nor was there a significant
reduction of VWF multimer size following incubation with
recombinant N700S fragments or platelet derived TSP-1
