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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2053-2058
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Identification of polymorphisms in the promoter and the 3' region
of the TAFI gene: evidence that plasma TAFI antigen levels
are strongly genetically controlled
Mireille Henry,
Hélène Aubert,
Pierre E. Morange,
Isabelle Nanni,
Marie-Christine Alessi,
Laurence Tiret, and
Irène Juhan-Vague
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,  2345 2G/1G, A-1690G, G-1102T, and G-438A) and 2 in the
3'UTR (C+1542G and T+1583A). All these polymorphisms were in strong linkage disequilibrium with each other and with the previously described Ala147Thr polymorphism. They generated 4 main haplotypes, accounting for 80% of all observed haplotypes. In univariate analyses, all polymorphisms were associated with plasma TAFI Ag levels and, individually, contributed to a large fraction of plasma TAFI Ag levels,
ranging from 20% to 52%. In a stepwise regression analysis including
all polymorphisms, several combinations remained significantly and
independently associated with plasma TAFI Ag levels: C+1542G associated
with Ala147Thr, T+1583A, or 2345 2G/1G explaining 61.6%, 60.2%, and
58.1% of the variance, respectively. These findings clearly
demonstrate that circulating levels of TAFI are strongly determined by
polymorphic variations in the promoter and the 3'UTR of the
TAFI gene.
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