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 activatedcells, that mediates the interaction of activated endothelial cells orplatelets with leukocytes. P-selectin expression is increased inatherosclerotic plaques, and high plasma levels of this molecule have beenobserved in patients with unstable angina. We investigated the P-selectingene as a possible candidate for myocardial infarction (MI). The P-selectingene is situated on chromosome 1q21-q24, spans >50 kb and contains 17exons. The sequences of the 5'-flanking region and exons of 40 alleles frompatients with MI were screened for polymorphisms using polymerase chainreaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing.Thirteen polymorphisms were identified: five in the 5'-flanking and eightin the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp,Leu599Val and Thr715Pro) predicted a change in the amino acid sequence ofthe P- selectin protein. All P-selectin polymorphisms as well as a commonE- selectin polymorphism, Ser128Arg which has been reported as beingassociated with an increased risk of premature coronary heart disease(CHD), and is in tight linkage disequilibrium with several P-selectinpolymorphisms, were investigated in 647 patients with MI and 758 controlsubjects from four regions of France and Northern Ireland (the ECTIMstudy). The entire set of P-selectin polymorphisms provided aheterozygosity of 91%. The polymorphisms were tightly associated with oneanother and displayed patterns of linkage disequilibrium suggesting theexistence of highly conserved ancestral haplotypes. The five polymorphismsin the 5'-flanking region of the gene were unrelated to MI or any relevantphenotype measured in the ECTIM study. We inferred that the four missensevariants identified in the coding region predicted eight common forms ofthe P-selectin protein. The Pro715 allele which characterizes one of theseforms 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 correctionfor the number of tests). We conclude that the P-selectin gene is highlypolymorphic and hypothesize that the Pro715 variant may be protective forMI. Whether this variant affects the properties of the P-selectin proteinin a way which is compatible with this hypothesis needs to be checkedexperimentally.