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Thromb Haemost 2000; 84(02): 150-155
DOI: 10.1055/s-0037-1613990
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Identification of Eight Novel Single-Nucleotide Polymorphisms at Human Tissue-type Plasminogen Activator (t-PA) Locus: Association with Vascular t-PA Release In Vivo

Per Ladenvall
1   From the Heart and Lung Institute, Clinical Experimental Research Laboratory, Göteborg, Sweden
,
Ulrika Wall
1   From the Heart and Lung Institute, Clinical Experimental Research Laboratory, Göteborg, Sweden
,
Sverker Jern
1   From the Heart and Lung Institute, Clinical Experimental Research Laboratory, Göteborg, Sweden
,
Christina Jern
1   From the Heart and Lung Institute, Clinical Experimental Research Laboratory, Göteborg, Sweden
2   Institute of Clinical Neuroscience, Department of Neurology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden
› Author AffiliationsWe thank T. Martinsson and J. Wahlström for reading an earlier version of the manuscript, M. Nordling for advice regarding genetic analyses, S. Nilsson for help in calculating linkage disequilibrium measures, and C. Ejdestig, H. Korhonen, and A. Johansson for excellent technical assistance. This work was supported by the Swedish Medical Research Council (09046), the Bank of Sweden Tercentenary Foundation, the Swedish Heart-Lung Foundation, the 1987 Stroke Foundation, the Magnus Bergvall Foundation, the Rune & Ulla Amlöv Foundation, the John& Brit Wennerström Foundation, the Göteborg Medical Society, and the Swedish Hypertension Society. By the time of the study, C. J. was a recipient of a postdoctoral fellowship from the Berth von Kantzow Foundation.
Further Information

Publication History

Received 30 March 2000

Accepted after revision 15 May 2000

Publication Date:
14 December 2017 (online)

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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.

Keywords

Tissue-type plasminogen activator - genetics - single-nucleotide polymorphism (SNP) - enhancer - Sp1

Part of this work was presented at the XVIIth Congress of the International Society on Thrombosis and Haemostasis, Washington D.C., August, 1999, and at the XXth Congress of American Society of Human Genetics, San Francisco, October, 1999.


 

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