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Social Bookmarking                   What's this?  Previous Article  |  Table of Contents Blood, 1 March 2002, Vol. 99, No. 5, pp. 1878-1878 CORRESPONDENCE To the editor: Thr325Ile polymorphism of the TAFI gene does not influence the risk of myocardial infarction Plasma TAFI antigen (Ag) levels are almost entirely under the control of the TAFI gene.1-3 Several polymorphisms found to be associated with TAFI Ag levels have been already described,1-4 but a recently performed segregation-linkage analysis indicates that the TAFI-linked quantitative trait loci is unlikely to be one of these already identified polymorphisms.5 Recently, Brouwers et al reported the identification a new polymorphism, 1040C/T, in the coding region of the TAFI gene that results in the Thr325Ile substitution.6 This polymorphism is of particular interest because, besides its association with TAFI plasma levels, studies using recombinant proteins have demonstrated a functional effect of the Thr325Ile substitution on the stability of activated TAFI resulting in altered antifibrinolytic activity, TAFI-Ile325 having a 60% greater antifibrinolytic activity than TAFI-Thr325.7 We evaluated the contribution of this polymorphism to the risk of myocardial infarction (MI) using a large European multicentric case-control study, the HIFMECH study. It consisted of white male patients younger than 60 years who survived a first MI (excluding patients with familial hypercholesterolemia and insulin-dependent diabetes mellitus) and population-based men of the same age recruited from 4 different centers (Stockholm, London, Marseilles, San Giovanni Rotondo). Consecutive patients were invited to participate along with randomly selected healthy individuals from the same catchment areas. In all, a total of 533 postinfarction patients and 575 controls were included in the study. Patients were studied 3 to 6 months after the acute event. Patients and control subjects were examined in parallel in the early morning after an overnight fast. Genotyping was performed in 1096 individuals, and citrate plasma was available for TAFI Ag determination in 914 individuals. In controls, the genotype distribution of Thr325Ile polymorphism was in Hardy-Weinberg equilibrium in each center, and there was no significant evidence of a difference in this distribution by center (P = .14), the overall frequency of the Ile allele being 0.31 (95% CI, 0.28-0.34). This polymorphism was in strong linkage disequilibrium with the previously described Ala147Thr and C1542>G polymorphisms of the TAFI gene (D' = 0.34 and +0.83 respectively; P < .001).2,4 In the sample as a whole, we confirmed the relationship between the 1040C/T polymorphism and TAFI Ag levels: Thr allele carriers presenting higher TAFI Ag levels (Table 1) both in MI cases and in controls. Despite this, the allele frequency for the Thr325Ile polymorphism was not different between cases and controls in the entire cohort (Table 1) or in any of the 4 centers taken separately (data not shown).                                View this table: [in this window] [in a new window]   Table 1. Distribution of Thr325Ile polymorphism of the TAFI gene and association with plasma TAFI Ag levels in individuals with MI and controls In conclusion, in this large multicentric case/control study, the Thr325Ile polymorphism of the TAFI gene does not influence the risk of MI. But as pointed out by Brouwers et al,6 the fact that the Thr325 allele could have the opposite effect by increasing TAFI Ag levels and decreasing TAFI antifibrinolytic activity at the same time deserves to be further studied to assess its influence on the risk of thrombosis. Pierre E. Morange, Mireille Henry, Corinne Frere, and Irène Juhan-Vague, on behalf of the HIFMECH study group Correspondence: I. Juhan-Vague, Lab Hematol, CHU Timone, 13385 Marseille cedex 5, France; e-mail: ijuhan{at}ap-hm.fr References 1. Crainich P, Tang Z, Macy EM, et al. A polymorphism at position 438 in the promoter region of the 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. 2. 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[Abstract/Free Full Text]. 3. Franco RF, Fagundes MG, Meijers JCM, et al. Identification of polymorphisms in the 5'-untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis. Haematologica. 2001;86:510-517[Abstract/Free Full Text]. 4. Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M. Identification and characterization of two thrombin-activable fibrinolysis inhibitor isoforms. Thromb Haemost. 1998;80:949-955[Medline] [Order article via Infotrieve]. 5. Tregouet DA, Aubert H, Henry M, et al. Combined segregation-linkage analysis of plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels with TAFI gene polymorphisms. Hum Genet. 2001;109:191-197[CrossRef][Medline] [Order article via Infotrieve]. 6. Brouwers GJ, Vos HL, Leebeek FWG, et al. A novel, possibly functional, single nucleotide polymorphism in the coding region of the thrombin-activatable fibrinolysis inhibitor (TAFI) gene is also associated with TAFI levels. Blood. 2001;98:1992-1993[Free Full Text]. 7. Schneider M, Boffa M, Stewart R, Rahman ML, Koschinsky M, Nesheim M. Two naturally occurring variants of TAFI (Thr 325 and Ile 325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem. Prepublished on October 29, 2001, as 10.1074/jbc.M104444200. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Gils, M.-C. Alessi, E. Brouwers, M. Peeters, P. Marx, J. Leurs, B. Bouma, D. Hendriks, I. Juhan-Vague, and P. J. Declerck Development of a Genotype 325-Specific proCPU/TAFI ELISA Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1122 - 1127. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morange, P. E. Articles by Juhan-Vague, I. Search for Related Content PubMed PubMed Citation Articles by Morange, P. E. Articles by Juhan-Vague, I. Social Bookmarking                   What's this?

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