THE P-SELECTIN GENE IS HIGHLY POLYMORPHIC - REDUCED FREQUENCY OF THE PRO715 ALLELE CARRIERS IN PATIENTS WITH MYOCARDIAL-INFARCTION

P-selectin is an adhesion molecule, expressed at the surface of activa ted cells, that mediates the interaction of activated endothelial cell s 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 a nd contains 17 exons. The sequences of the 5'-flanking region and exon s of 40 alleles from patients with MI were screened for polymorphisms using polymerase chain reaction/single-strand conformation polymorphis m (PCR-SSCP) and sequencing. Thirteen polymorphisms were identified: f ive in the 5'-flanking and eight in the exonic sequences. Four polymor phisms (Ser290Asn, Asn562Asp, Leu599Val and Thr715Pro) predicted a cha nge in the amino acid sequence of the P-selectin protein. All P-select in polymorphisms as well as a common E-selectin polymorphism, Ser128Ar g which has been reported as being associated with an increased risk o f premature coronary heart disease (CHD), and is in tight linkage dise quilibrium with several P-selectin polymorphisms, were investigated in 647 patients with MI and 758 control subjects from four regions of Fr ance and Northern Ireland (the ECTIM study). The entire set of P-selec tin polymorphisms provided a heterozygosity of 91%, The polymorphisms were tightly associated with one another and displayed patterns of lin kage disequilibrium suggesting the existence of highly conserved ances tral haplotypes. The five polymorphisms in the 5'-flanking region of t he gene were unrelated to MI or any relevant phenotype measured in the ECTIM study. We inferred that the four missense variants identified i n the coding region predicted eight common forms of the P-selectin pro tein. The Pro715 allele which characterizes one of these forms was les s 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. Whe ther this variant affects the properties of the P-selectin protein in a way which is compatible with this hypothesis needs to be checked exp erimentally.