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Blood, 1 January 2008, Vol. 111, No. 1, pp. 183-189.
Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-03-078543.
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Submitted March 8, 2007
Accepted August 24, 2007
Effect of single nucleotide polymorphisms on expression of the gene encoding thrombin activatable fibrinolysis inhibitor: a functional analysis
Michael B Boffa*, Deborah Maret, Jeffrey D Hamill, Nazareth Bastajian, Paul Crainich, Nancy S Jenny, Zhonghua Tang, Elizabeth M Macy, Russell P Tracy, Rendrik F Franco, Michael E Nesheim, and Marlys L Koschinsky
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
Department of Pathology, College of Medicine, University of Vermont, Colchester, VT, United States
Department of Biochemistry, College of Medicine, University of Vermont, Colchester, VT, United States
Fleury Research Institute, Sao Paolo, Brazil
Department of Medicine, Queen's University, Kingston, Ontario, Canada
* Corresponding author; email: boffam{at}post.queensu.ca.
Thrombin-activable fibrinolysis inhibitor (TAFI) is a plasma zymogen that acts as a molecular link between coagulation and fibrinolysis. Numerous single nucleotide polymorphisms (SNPs) have been identified in CPB2, the gene encoding TAFI, and are located in the 5'-flanking region, in the coding sequences, and in the 3'-untranslated region (UTR) of the CPB2 mRNA transcript. Associations between CPB2 SNPs and variation in plasma TAFI antigen concentrations have been described but the identity of SNPs that are causally linked to this variation is not known. In the current study, we investigated the effect of the SNPs in the 5'-flanking region on CPB2 promoter activity and SNPs in the 3'-UTR on CPB2 mRNA stability. Whereas the 5'-flanking region SNPs (with 2 exceptions) did not have a significant effect on promoter activity, either alone or in haplotypic combinations seen in the human population, all of the 3'-UTR SNPs substantially affected mRNA stability. We speculate that these SNPs, in part, contribute to variation in plasma TAFI concentrations via modulation of CPB2 gene expression through an effect on mRNA stability.
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