Herrmann S M, Ricard S, Nicaud V, Mallet C, Evans A, Ruidavets J B, Arveiler D, Luc G, Cambien F
INSERM SC7, 17 rue du Fer à Moulin, 75005 Paris, France.
Hum Mol Genet. 1998 Aug;7(8):1277-84. doi: 10.1093/hmg/7.8.1277.
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.
P-选择素是一种粘附分子，在活化细胞表面表达，介导活化的内皮细胞或血小板与白细胞的相互作用。P-选择素在动脉粥样硬化斑块中的表达增加，并且在不稳定型心绞痛患者中观察到该分子的血浆水平升高。我们研究了P-选择素基因作为心肌梗死（MI）的一个可能候选基因。P-选择素基因位于1号染色体的1q21-q24区域，跨度大于50kb，包含17个外显子。使用聚合酶链反应/单链构象多态性（PCR-SSCP）和测序技术，对心肌梗死患者的40个等位基因的5'-侧翼区域和外显子序列进行多态性筛选。共鉴定出13个多态性位点：5个在5'-侧翼区域，8个在外显子序列中。4个多态性位点（Ser290Asn、Asn562Asp、Leu599Val和Thr715Pro）预测P-选择素蛋白的氨基酸序列会发生变化。在来自法国四个地区和北爱尔兰的647例心肌梗死患者和758例对照受试者（ECTIM研究）中，研究了所有P-选择素多态性以及一种常见的E-选择素多态性Ser128Arg，该多态性已被报道与早发冠心病（CHD）风险增加相关，并且与几种P-选择素多态性处于紧密连锁不平衡状态。整套P-选择素多态性的杂合度为91%。这些多态性位点彼此紧密相关，并显示出连锁不平衡模式，提示存在高度保守的祖先单倍型。该基因5'-侧翼区域的5个多态性位点与心肌梗死或ECTIM研究中测量的任何相关表型均无关。我们推断在编码区鉴定出的4个错义变体预测了P-选择素蛋白的8种常见形式。表征其中一种形式的Pro715等位基因在法国的频率低于北爱尔兰（P<0.002），在病例组中的频率低于对照组（P<0.002；经检验次数校正后P<0.02）。我们得出结论，P-选择素基因具有高度多态性，并推测Pro
