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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
From the Laboratoire d'Hématologie, INSERM EPI
99-36, Marseilles, and INSERM U525, Paris, France.
Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently
described carboxypeptidase that is potentially involved in the
regulation of fibrinolysis by decreasing plasminogen binding to the
fibrin surface. This role makes the TAFI gene a good
candidate in atherothrombotic diseases. The great interindividual
variability of plasma TAFI antigen levels is poorly explained by
lifestyle characteristics, thus suggesting its genetic determination.
To test this hypothesis, the promoter and the 3'-untranslated region of
the TAFI gene were screened for polymorphisms, and their
contribution to the variability of plasma TAFI antigen levels was
evaluated. Seven new polymorphisms are described, 5 in the promoter
(C-2599G, Thrombin-activable fibrinolysis inhibitor (TAFI),
also known as procarboxypeptidase B and procarboxypeptidase U, is a
recently described plasma protein that can potentially inhibit
fibrinolysis by removing carboxyterminal lysine residues from partially
degraded fibrin, decreasing plasminogen binding on its
surface.1-4 TAFI is secreted by the liver as a zymogen and
can be efficiently activated by the thrombin-thrombomodulin complex in
vitro. Because of its role in the balance between the coagulation and
the fibrinolytic systems, the TAFI gene may be considered a
potential candidate in atherothrombotic diseases. Studies in a rabbit
jugular vein model of thrombolysis revealed that inhibition of
activated TAFI activity increased therapeutic
fibrinolysis.5,6 Moreover, it has been recently shown that
high levels of TAFI antigen (Ag) could be a risk factor for venous
thrombosis.7
A study conducted in consecutive patients attending a metabolic ward
for primary prevention showed a great interindividual variability
in plasma TAFI Ag levels, which appeared to be poorly explained by
lifestyle characteristics (2% and 3% in men and women, respectively).8 This weak influence of environmental
factors suggested that TAFI variations could be genetically determined.
The human TAFI gene is located on chromosome 13q14.11 and
consists of 11 exons spanning approximately 48 kb. The sequence of its
promoter and 3'-untranslated region (3'UTR) has been recently published.9 Until now, only 2 polymorphisms in the coding
sequence have been described: one is a G-to-A substitution at
nucleotide 505 on the cDNA sequence, leading to an Ala-to-Thr
substitution at amino acid 147, and the other is a C-to-T substitution
at nucleotide 678, resulting in a silent polymorphism.10
In vitro studies did not show any effect of the Ala147Thr substitution
on kinetics of activation of TAFI by thrombin-thrombomodulin complex.
However, its effect on the protein level has not been assessed yet.
The aim of our study was to screen the promoter and the 3'UTR of the
TAFI gene for polymorphisms and to evaluate their
contribution to plasma TAFI Ag variability with the recently described
Ala147thr polymorphism.
Study population
TAFI antigen determination
Search for novel polymorphisms in the TAFI gene by PCR-SSCP and sequencing For the screening of the TAFI gene, we compared genomic DNA from 40 healthy subjects recruited from a systematic screening of a healthy population.11 Twenty subjects with high and 20 subjects with low plasma TAFI Ag levels (200% ± 24%; 60% ± 7%, respectively) were included. These sets of DNA were not part of the studied population.Genomic DNA was extracted from peripheral blood leukocytes by the
salting-out method.12 The sequenced promoter
region9 was divided into 10 overlapping fragments of
approximately 300 bp maximum, as shown in Figure
1. Amplified DNA fragments larger than
this were digested with appropriate restriction endonucleases (Table
1). Fragments were amplified and
biotin-labeled during amplification. The 3'UTR was screened in one DNA
fragment using the direct primer at the end of exon 10, just before the
first TAA stop signal of the translation, and the reverse primer after the last signal of polyadenylation. The sequence of the 3'UTR was
obtained by the addition of the cDNA sequence published by Eaton et
al13 and of the genomic sequence published by Boffa et
al.9 Primer sequences, lengths, locations of amplified
fragments, and annealing temperatures are reported in Table 1. When a
shift in the pattern of migration was observed, 2 or 3 sets of DNA
corresponding to the different patterns were amplified and directly
sequenced. Polymorphisms located in the promoter were numbered from the
start of transcription according to the published
sequence.9 Polymorphisms located in the 3'UTR were
numbered from the first ATG located in position 19 on the cDNA sequence
published in GenBank (accession number NM001872).
Analysis was performed with the procedure previously described.14 Briefly, each DNA was amplified with dUTP biotin incorporation, then, after a 5-minute denaturation at 95°C, they were loaded on 6% or 10% polyacrylamide gel with or without glycerol. A nondenaturing buffer (TBE, 0.5×) was used, and electrophoresis was performed at room temperature. Then DNA was transferred on a nylon membrane and revealed by the alkaline-phosphatase-streptavidin-NBT-BCIP procedure. All potential band shifts were analyzed by direct sequencing of a separately amplified fragment, using ABI Prism Bigdye Terminator and ABI Prism 377 sequencer (PE Biosystems, Foster City, CA). Allele-specific polymerase chain reaction analyses Genotyping of polymorphisms in the promoter and the 3'UTR was performed using allele-specific polymerase chain reactions (PCR). A PCR was performed for each allele determination according to the following conditions. Amplification was carried out in 25 µL in a Thermocycler 9600 Perkin Elmer (Applied Biosystems, Foster City, CA). Each sample contained 62 ng genomic DNA in 1× Taq polymerase buffer (3.5 mM MgCl2), 0.77 mM dNTP, 5 pmol each primer (forward and reverse primers in each case plus the allele-specific primer that corresponds to the analyzed genotype), and 0.38-U Taq polymerase (Biotaq; Quantum Bioprobe, Quebec Canada). A first denaturation at 95°C for 2 minutes was followed by 40 cycles for 1 minute at annealing temperature (determined for each reaction), at 72°C for 1 minute (extension), at 95°C for 45 seconds (denaturation), and then at 72°C for 5 minutes. All primer sequences and annealing temperatures are described in Table 2. Five microliters of each amplification sample was loaded on a 2% agarose gel stained with ethidium bromide.
For some polymorphisms, modifications were brought to this procedure. For the A-1690G polymorphism, we used 2.5 pmol forward primer to obtain better sensitivity. For the C+1542G polymorphism, the allele-specific primers were chosen in reverse sequence to obtain specific amplification. Because the intronic sequence flanking the Ala147Thr polymorphism is unknown, genotyping of this polymorphism was performed by using only one allele-specific and one reverse primer. C+1542G direct and reverse primers were used concomitantly as an internal control of amplification. Statistical analysis Data were analyzed using the SAS software (SAS Institute, Cary, NC). Allele frequencies were estimated by gene counting. Hardy-Weinberg equilibrium was tested by 2 analysis
with 1 df. Pairwise linkage disequilibrium coefficients between polymorphisms were estimated by log-linear model
analysis,15 and the extent of disequilibrium was expressed
in terms of D' = D/Dmax or  D/Dmin.
Haplotype frequencies were estimated and compared between TAFI
tertiles using the Arlequin software (Arlequin [computer
program]. Version 2000. Geneva, Switzerland: University of Geneva;
2000). Association of polymorphisms with TAFI Ag levels was
tested by analysis of variance. The distribution of TAFI levels was
log-transformed to remove positive skewness, and geometric means (95%
confidence interval) were provided. Multivariate regression analysis
was performed to assess the independent effect of several polymorphisms
considered together. A codominant model assuming additive allele
effects of polymorphisms on log(TAFI) was tested. Because this model
was well fitted to the data for all the polymorphisms, it was adopted
in all genotype-phenotype association analyses.
Systematic search for polymorphisms of the TAFI gene promoter We divided the sequenced promoter region into 10 overlapping fragments, as shown in Figure 1. These fragments were amplified and biotin labeled during amplification. The PCR-SSCP analysis was performed with 40 genomic DNA, 20 from subjects with a high TAFI antigen plasma level (200% ± 24%), and 20 subjects with a low TAFI antigen plasma level (60% ± 7%), in 2 experiments. When a shift in the pattern of migration was observed, 2 or 3 sets of DNA corresponding to the different patterns were amplified and direct sequenced. Five frequent polymorphisms were identified in the promoter: a C-to-G substitution at position2599 upstream from the start of
transcription, an insertion-deletion of one G nucleotide at position
2345, an A-to-G substitution at position 1690, a G-to-T
substitution at position 1102, and a G-to-A substitution at position
438 (Figure 1).
3'UTR For this analysis we chose a DNA fragment starting from the end of exon 10 just before the first TAA stop signal of the translation and ending at the last signal of polyadenylation. Two polymorphisms were identified in the 3'UTR: a C-to-G substitution at nucleotide +1542 of the cDNA sequence published by Eaton13 and a T-to-A substitution at position +1583 (Figure 1). None of the genomic DNA sequenced contained the sequence TCTTCTCCTTT, which spans nucleotides 1680 to 1690 of the published cDNA sequence. We found sequence TGCACG instead of TCAG between nucleotide 1403 to 1405 on all the sequenced genomic DNA.Allele frequencies and linkage disequilibrium between polymorphisms Genotype distribution did not deviate from Hardy-Weinberg expectations, except for the Ala147Thr polymorphism for which a slight excess of heterozygotes was observed (P < .02). All polymorphisms were common; frequency of the minor allele ranged from 0.24 to 0.49 (Table 3). All polymorphisms were in strong linkage disequilibrium with each other (Table 3). A-1690G, G-1102T, and G-438A were in almost complete concordance, and, consequently, only the G-438A polymorphism was considered in further analyses.
The 6 remaining polymorphisms generated 4 main haplotypes, accounting
for more than 80% of all the haplotypes observed in the whole sample
(Table 4). None of the other observed
haplotypes had a frequency higher than 5%. Within the 4 main
haplotypes, the
Association of TAFI polymorphisms with plasma TAFI Ag levels All the polymorphisms were strongly associated with TAFI Ag levels (P < 10 4). In all cases, the model was
compatible with an additive allele effect on the log-transformed
variable. Geometric means and 95% confidence intervals according to
genotypes are shown in Table 5. The
percentage of variance explained by genotypes varied from 52% for the
C+1542G polymorphism to 20% for the 2345 2G/1G polymorphism.
We then investigated by multivariate analysis whether several
polymorphisms were independently associated with TAFI levels. In a
stepwise regression analysis including all the polymorphisms, 2 remained significantly and independently associated with plasma TAFI Ag
levels, the C+1542G and the Ala147thr polymorphisms. Together, these 2 polymorphisms explained 61.6% of the variance. Two other pairs of
polymorphisms explained nearly the same percentage of TAFI variance:
the C+1542G polymorphism in combination either with the T+1583A
polymorphism (60.2%) or with the Frequencies of the 4 main haplotypes were compared between the 1st and
3rd tertiles of the TAFI distribution, and the difference was highly
significant (P < 10 Table 6 gives geometric TAFI means when
the C+1542G and the Ala147Thr polymorphisms are combined. An additive
effect of the 2 polymorphisms on TAFI levels was clearly shown (test on
interaction between genotypes, P = .77). An almost 3-fold
increase in TAFI Ag levels was observed between individuals combining
the +1542GG and 147Ala/Ala genotypes and those combining the +1542CC
and 147Ala/Thr genotypes (35.2 vs 98.5, respectively). The single
individual carrying the combination +1542CC and 147Thr/Thr had an even
higher TAFI level. However, it should be stressed again that the effect of the Ala147Thr polymorphism alone is not distinguishable from that of
the haplotype combining the Ala147Thr, the T+1583A, and the
TAFI is supposed to play a key role in the regulation of fibrinolysis through its potential to regulate plasminogen activation. Consequently, it has been suggested that high levels of TAFI could be a risk factor for atherothrombotic diseases. This hypothesis has been recently strengthened by a study showing a weak association between high TAFI levels and deep vein thrombosis.7 A great interindividual variability of plasma levels has been shown, weakly explained by environmental factors.8 This suggested a genetic determination of plasma TAFI concentrations. Here we screened the promoter and the 3'UTR of the human TAFI gene to identify polymorphisms linked to plasma TAFI levels. We described 7 new polymorphisms: 5 in the promoter, 2 in the
3'UTR. All these polymorphisms were in strong linkage disequilibrium with each other and with the previously described Ala147Thr
polymorphism. Because of the strong association between polymorphisms,
they generated 4 main haplotypes that accounted for 80% of all
haplotypes observed in the sample. In univariate analyses, all
polymorphisms were associated with plasma TAFI Ag levels and,
individually, contributed to a large fraction of plasma TAFI
variability, ranging from 20% to 52%. However, the multivariate
analysis suggested that at least 2 polymorphisms had independent and
additive effects on TAFI levels. When combining these 2 polymorphisms,
the percentage of variance explained reached more than 60%, indicating
a strong influence of the TAFI gene on the determination of
plasma TAFI levels. The polymorphisms that exhibited the highest
R2 in multivariate analysis included the C+1542G
and the Ala147Thr polymorphisms. Close R2 were
also observed when the C+1542G polymorphism was combined either with
the The results suggest that the regulation of plasma TAFI levels by the TAFI gene is complex and probably involves more than one single functional variant. The strong association observed between polymorphisms located within the promoter and the 3'UTR of the TAFI gene and TAFI Ag levels suggests that at least some of these polymorphisms are located within transcriptional regulatory regions. The role of the 2 polymorphisms within the 3'UTR in the mRNA stability can also be envisaged. However, we cannot exclude the possibility that the results observed in this study reflect the role of an unidentified functional polymorphism located elsewhere and that would be in linkage disequilibrium with all these polymorphisms. Further characterizations of sequence variations of the TAFI gene with in vitro experiments testing the functionality of the 5' and 3'UTR polymorphisms are needed. Our results must be compared to the study of the transcriptional
activity of the 5'-flanking region of the TAFI gene in
mammalian cells reported by Boffa et al.9 Transient
transfection assays of reporter plasmids containing portions of the
TAFI 5'-flanking region into mammalian cells identified an
approximately 70-bp region between nucleotides In accordance with the results reported by Boffa et al,9 none of the genomic DNA sequenced in our study contained the sequence TCTTCTCCTTT, which spans nucleotides 1680 to 1690 of the published cDNA sequence.13 Moreover, we found sequence TGCACG instead of TCAG between nucleotides 1403 and 1405 on all sequenced genomic DNA. In conclusion, this study showed that interindividual variations of plasma TAFI Ag levels are strongly genetically determined. We described 7 new polymorphisms, 5 in the promoter and 2 in the 3'UTR of the TAFI gene, that accounted for a large part of this genetic variability. In vitro studies are needed to evaluate the functional importance of these polymorphisms. Moreover, it will be important to assess the role of these polymorphisms in relation to arterial or venous thromboembolic diseases.
We thank V. Nicaud and D. A. Trégouët (INSERM U525) for their help in statistical analyses and M. Billerey and S. Debroas for their skillful assistance.
Submitted September 15, 2000; accepted November 27, 2000.
Supported by INSERM, the Commission of the European Community, Hifmech Study contract BMH4-CT96-0272, the Fondation pour la Recherche Médicale, the Programme Hospitalier de Recherche Clinique (PHRC 1996), and Université de la Méditerranée. H.A. is recipient of a grant from Diagnostica Stago and Association Nationale de la Recherche Technique, France (Convention CIFRE 407/99).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Irène Juhan-Vague, Laboratoire d'Hématologie, CHU Timone, 13385 Marseilles cedex 5, France.
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© 2001 by The American Society of Hematology.
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  M. E. Meltzer, C. J.M. Doggen, P. G. de Groot, J. C.M. Meijers, F. R. Rosendaal, and T. Lisman Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men Haematologica, June 1, 2009; 94(6): 811 - 818. [Abstract] [Full Text] [PDF]
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 C. Ladenvall, A. Gils, K. Jood, C. Blomstrand, P. J. Declerck, and C. Jern Thrombin Activatable Fibrinolysis Inhibitor Activation Peptide Shows Association With All Major Subtypes of Ischemic Stroke and With TAFI Gene Variation Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 955 - 962. [Abstract] [Full Text] [PDF]
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C. Frere, D.-A. Tregouet, P.-E. Morange, N. Saut, D. Kouassi, I. Juhan-Vague, L. Tiret, and M.-C. Alessi Fine mapping of quantitative trait nucleotides underlying thrombin-activatable fibrinolysis inhibitor antigen levels by a transethnic study Blood, September 1, 2006; 108(5): 1562 - 1568. [Abstract] [Full Text] [PDF]
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B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]
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L. O. Mosnier, P. Buijtenhuijs, P. F. Marx, J. C. M. Meijers, and B. N. Bouma Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets Blood, June 15, 2003; 101(12): 4844 - 4846. [Abstract] [Full Text] [PDF]
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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]
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I. Juhan-Vague, P.E. Morange, H. Aubert, M. Henry, M.F. Aillaud, M.C. Alessi, A. Samnegard, E. Hawe, J. Yudkin, M. Margaglione, et al. Plasma Thrombin-Activatable Fibrinolysis Inhibitor Antigen Concentration and Genotype in Relation to Myocardial Infarction in the North and South of Europe Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 867 - 873. [Abstract] [Full Text] [PDF]
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P. E. Morange, M. Henry, C. Frere, and I. Juhan-Vague Thr325Ile polymorphism of the TAFI gene does not influence the risk of myocardial infarction Blood, March 1, 2002; 99(5): 1878 - 1878. [Full Text] [PDF]
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G.-J. Brouwers, H. L. Vos, F. W. G. Leebeek, S. Bulk, M. Schneider, M. Boffa, M. Koschinsky, N. H. van Tilburg, M. E. Nesheim, R. M. Bertina, 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, September 15, 2001; 98(6): 1992 - 1993. [Full Text] [PDF]
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Abstract
Introduction