title: Effect of single nucleotide polymorphisms on expression of the gene encoding thrombin-activatable fibrinolysis inhibitor: a functional analysis.
abstract: 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.
authors.affiliation: Department of Biochemistry, Queen's University, Kingston, ON, Canada. boffam@post.queensu.ca
authors.forename: Michael B
authors.initials: MB
authors.lastname: Boffa
authors.forename: Deborah
authors.initials: D
authors.lastname: Maret
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hamill
authors.forename: Nazareth
authors.initials: N
authors.lastname: Bastajian
authors.forename: Paul
authors.initials: P
authors.lastname: Crainich
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Jenny
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Tang
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Macy
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Rendrik F
authors.initials: RF
authors.lastname: Franco
authors.forename: Michael E
authors.initials: ME
authors.lastname: Nesheim
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D025901:Carboxypeptidase B2 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008156:Luciferases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D008156:Luciferases; D025901:Carboxypeptidase B2