Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus:: Association with vascular t-PA release in vivo
Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus:: Association with vascular t-PA release in vivo
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DOI：
10.1055/s-0037-1613990
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发表时间：
2000-08-01
影响因子：
6.7
通讯作者：
Jern, C
中科院分区：
文献类型：
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作者：
Ladenvall, P;Wall, U;Jern, C
最近，我们报道了组织型纤溶酶原激活物（t-PA）基因的Alu插入多态性与人类血管t-PA释放率相关。在目前的研究中，我们在t-PA基因中寻找具有这种多态性的连锁不平衡（LD）假定的功能遗传变异。研究了不同Alu基因型的健康个体及其t-PA释放率的差异。对t-PA基因的调控区和编码区进行了测序。鉴定出8个单核苷酸多态性（snp）。其中3个与Alu多态性呈显著LD，因此与t-PA释放率相关；一个在远上游的增强子上，一个在外显子6上，一个在内含子10上。增强子SNP驻留在GC盒中。电泳迁移率转移分析（EMSA）显示Spl与T等位基因的结合亲和力降低，而T等位基因是T - pa释放率低的等位基因。外显子6和内含子10的变化是沉默的，对剪接没有明显的影响。
Recently, we reported that an Alu insertion polymorphism of the tissue-type plasminogen activator (t-PA) gene is associated with vascular t-PA release rates in man. In the current study we searched the t-PA gene for putative functional genetic variants in linkage disequilibrium (LD) with this polymorphism. Healthy individuals with different Alu genotypes and contrasting t-PA release rates were studied. Regulatory and coding regions of the t-PA gene were sequenced. Eight single-nucleotide polymorphisms (SNPs) were identified. Three of these were in significant LD with the Alu polymorphism and consequently associated with t-PA release rates; one in the far upstream enhancer, one in exon 6, and one in intron 10. The enhancer SNP resides within a GC box. Electrophoretic mobility shift assay (EMSA) revealed a reduced binding affinity of Spl to the T allele, which is the allele associated with a low t-PA release rate. Variations in exon 6 and intron 10 were silent and without apparent effect on splicing, respectively.