Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo.

P Ladenvall, U Wall, S Jern, C Jern

Journal: Thrombosis and haemostasis 2001;84(2):150-5

PMID: 10959683

Abstract

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 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.

Address: Heart and Lung Institute, Clinical Experimental Research Laboratory, Sahlgrenska University Hospital, Göteburg University, Sweden.

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MeSH Terms: Alu Elements, Binding Sites, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Endothelium, Vascular, Gene Frequency, Genetic Variation, Genotype, Heterozygote, Homozygote, Humans, Linkage Disequilibrium, Multigene Family, Phenotype, Polymorphism, Genetic, Promoter Regions, Genetic, Sp1 Transcription Factor, Sweden, Tissue Plasminogen Activator, Transcription Factors, White People, Zinc Fingers