title: Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo.
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.
authors.affiliation: Heart and Lung Institute, Clinical Experimental Research Laboratory, Sahlgrenska University Hospital, Göteburg University, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Ladenvall
authors.forename: U
authors.initials: U
authors.lastname: Wall
authors.forename: S
authors.initials: S
authors.lastname: Jern
authors.forename: C
authors.initials: C
authors.lastname: Jern
mesh_terms: D020087:Alu Elements / Q000235:genetics; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D005810:Multigene Family / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013548:Sweden / Q000453:epidemiology; D010959:Tissue Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D010959:Tissue Plasminogen Activator