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CORRESPONDENCE In a recent issue of Blood, Henry et al1 reported
the identification of several single nucleotide polymorphisms (SNPs) in
the promoter and 3' untranslated region of the
thrombin-activatable fibrinolysis inhibitor (TAFI)
gene. They also investigated the 505A/G SNP in the coding
region of the TAFI gene resulting in an amino acid (aa)
substitution, Thr147Ala.2 Henry et al1 showed
that plasma TAFI antigen (Ag) levels are strongly
associated with all these SNPs that turned out to be in strong linkage
disequilibrium. This association confirmed and extended
preliminary reports on the association of TAFI plasma levels and SNPs
in the TAFI gene promoter.3,4 We identified another SNP, 1040C/T, in the coding region of the
TAFI gene by comparing published sequences (GenBank no.
NM_001872 and NM_016413). This SNP also results in an aa substitution
(Thr325Ile). This SNP is of particular interest because it has been
shown that the presence of an Ile325 residue has a positive influence
on both TAFIa activity and stability in vitro resulting in
increased antifibrinolytic activity.5 On the contrary, the
Thr147Ala substitution has no effect on the functional properties of
TAFI in vitro.2 We determined in a group of 152 blood donors (mean age 45.8 years, SD
11.7, range 19-71 years, 94 males and 58 females) the genotype
frequency and allele frequency of the 1040C/T SNP and correlated this
with TAFI Ag levels.6 The 1040C/T SNP was significantly associated with TAFI Ag levels with
the C/C genotype corresponding with the highest and the T/T genotype
with the lowest TAFI Ag levels (Table 1). The 1040C/C
genotype corresponds to Thr/Thr at position 325. Activated TAFI-Thr325
has a normal in vitro half-life of 8 minutes (at 37°C), whereas
activated TAFI-Ile325 has a half-life of about 16 minutes and a 60%
greater antifibrinolytic activity compared to
TAFI-Thr325.5 The reduced antifibrinolytic
activity of TAFI-Thr325 is very likely the result of the greater
instability of this isoform. It is remarkable that the Thr325 allele,
which is associated with increased TAFI Ag levels in vivo, encodes a
TAFI isoform that is less stable after activation in vitro. At present,
it is not known whether the substitution of Thr325Ile will make TAFI
less susceptible to degradation by plasmin via an effect on the
cleavage at Arg328.7
To determine if the 1040C/T SNP is in linkage disequilibrium with the
SNPs studied by Henry et al,1 we also determined the
genotype and allele frequencies of the In conclusion, the 1040T/C SNP located in the coding region of the TAFI gene and resulting in the Thr325Ile substitution is associated with TAFI plasma levels, just like other SNPs in and around this gene. Presently, it is not known which SNP is/are responsible for this effect on TAFI levels. On the other hand, studies using recombinant proteins have demonstrated a functional effect of the Thr325Ile substitution on the stability of activated TAFI resulting in altered antifibrinolytic activity. The possibility that the same TAFI haplotype will affect levels and antifibrinolytic activity in opposite directions will hamper the interpretation of genetic association studies using this SNP.
Geert-Jan Brouwers, Hans L. Vos, Frank W. G. Leebeek, Saskia Bulk, Mark Schneider, Michael Boffa, Marlys Koschinsky, Nico H. van Tilburg, Michael E. Nesheim, Rogier M. Bertina, and Encarnación B. Gómez
García
References
1.
Henry M, Aubert H, Morange PE, et al.
Identification of polymorphisms in the promoter and the 3' region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled.
Blood.
2001;97:2053-2058 2. Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb Haemost. 1998;80:949-955[Medline] [Order article via Infotrieve]. 3. Franco RF, Fagundes MG, Meijers JCM, et al. Identification of polymorphisms in the TAFI gene promoter; relationship with plasma TAFI levels and risk of venous thrombosis [abstract]. Blood. 2000;96:565a. 4. Crainich P, Tang Z, Macy EM, et al. A polymorphism at position -438 in the promoter region of thrombin-activatable fibrinolysis inhibitor (TAFI) is strongly associated with plasma antigen levels in healthy older men and women [abstract]. Circulation. 2000;102(suppl II):866. 5. Schneider MS, Boffa MB, Rahman MN, et al. A variant of human TAFI exhibits increased thermal stability and increased antifibrinolytic potential [abstract]. Thromb Haemost (CD-ROM). July 2001 (suppl). Abstract OC1756.
6.
van Tilburg NH, Rosendaal FR, Bertina RM.
Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.
Blood.
2000;95:2855-2859 7. Marx PF, Bouma BN, Meijers JCM. Plasmin mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor [abstract]. Blood. 2000;96:44a.   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
438A/G TAFI
promoter SNP and the 505A/G SNP in the coding region of the
TAFI gene. The 
2
analysis). The 
