Human Molecular Genetics, Vol 7, 1277-1284, Copyright © 1998 by Oxford University Press
SM Herrmann, S Ricard, V Nicaud, C Mallet, A Evans, JB Ruidavets, D Arveiler, G Luc and F Cambien
P-selectin is an adhesion molecule, expressed at the surface of activated
cells, that mediates the interaction of activated endothelial cells or
platelets with leukocytes. P-selectin expression is increased in
atherosclerotic plaques, and high plasma levels of this molecule have been
observed in patients with unstable angina. We investigated the P-selectin
gene as a possible candidate for myocardial infarction (MI). The P-selectin
gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17
exons. The sequences of the 5'-flanking region and exons of 40 alleles from
patients with MI were screened for polymorphisms using polymerase chain
reaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing.
Thirteen polymorphisms were identified: five in the 5'-flanking and eight
in the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp,
Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of
the P- selectin protein. All P-selectin polymorphisms as well as a common
E- selectin polymorphism, Ser128Arg which has been reported as being
associated with an increased risk of premature coronary heart disease
(CHD), and is in tight linkage disequilibrium with several P-selectin
polymorphisms, were investigated in 647 patients with MI and 758 control
subjects from four regions of France and Northern Ireland (the ECTIM
study). The entire set of P-selectin polymorphisms provided a
heterozygosity of 91%. The polymorphisms were tightly associated with one
another and displayed patterns of linkage disequilibrium suggesting the
existence of highly conserved ancestral haplotypes. The five polymorphisms
in the 5'-flanking region of the gene were unrelated to MI or any relevant
phenotype measured in the ECTIM study. We inferred that the four missense
variants identified in the coding region predicted eight common forms of
the P-selectin protein. The Pro715 allele which characterizes one of these
forms was less frequent in France than in Northern Ireland ( P < 0.002)
and in cases than in controls ( P < 0.002; P < 0.02 after correction
for the number of tests). We conclude that the P-selectin gene is highly
polymorphic and hypothesize that the Pro715 variant may be protective for
MI. Whether this variant affects the properties of the P-selectin protein
in a way which is compatible with this hypothesis needs to be checked
experimentally.
ARTICLES
The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction
INSERM SC7, 17 rue du Fer a Moulin, 75005 Paris, France. herrmann@idf.inserm.fr
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