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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Abstract
Summary: 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 singlenucleotide 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 Sp1 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.
Funding Information
  • Swedish Medical Research Council ((09046))
  • Bank of Sweden Tercentenary Foundation
  • Swedish Heart-Lung Foundation
  • Stroke Foundation
  • Magnus Bergvall Foundation
  • Rune & Ulla Amlöv Foundation
  • John& Brit Wennerström Foundation
  • Göteborg Medical Society
  • Swedish Hypertension Society
  • Berth von Kantzow Foundation

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