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Effect of genetic variants in the TAFI gene on TAFI levels, the efficiency and safety of anticoagulant therapy in patients with venous thromboembolism in Russian population
Vorobyeva N. M.1, Dobrovolsky A. B.1, Doroshchuk N. A.1, Khasanova Z. B.1, Titaeva E. V.1, Kirienko A. I.2, Panchenko E. P.1 1Russian Cardiology Research and Production Complex, 2Russian State Medical University, Moscow, Russian Federation
Abstract
Materials & Methods
Results (Cont.)
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Background. Several studies have reported that thrombin activatable fibrinolysis inhibitor (TAFI) levels may be partly determined genetically. Results from these studies are conflicting. The influence of TAFI genetic variants on the efficiency and safety of anticoagulant therapy is not yet clear.
Aims. To determine the frequency of the TAFI gene polymorphisms and theirs effect on TAFI levels, the efficiency and safety of anticoagulant therapy in pts with venous thromboembolism in Russian population.
Methods. One hundred and eleven pts (76 men) in the age (mean 54 ± 14) years with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were included in the study. Pts received unfractionated or low molecular weight heparin for at least 5 days followed by long-term warfarin therapy (international normalized ratio 2,0-3,0). TAFI levels were measured at baseline by a chromogenic assay with reagent kits «STA STACHROM TAFI» (Diagnostica Stago). Three TAFI genetic polymorphisms (–438G/A, 505G/A and 1040C/T) were investigated. The follow-up period was 18 months. Endpoints were DVT/PE recurrences and hemorrhagic complications. Results of TAFI levels are presented as a median (interquartile range).
Results. In all pts, median of TAFI levels was 106 (90; 133) %. The frequency of –438GG, –438GA, –438AA genotypes was 67,6%, 29,7% and 2,7%; 505GG, 505GA, 505AA genotypes – 47,8%, 49,5% and 2,7%; 1040CC, 1040CT, 1040TT genotypes – 50,5%, 41,4% and 8,1% respectively. Univariate regression analysis showed that all three polymorphisms were associated with TAFI levels. For the –438G/A and 1040C/T variants, the carriers of rare alleles (–438A and 1040T) were associated with lower TAFI levels than common alleles (–438G and 1040C) – 98 (82; 118) vs 106 (89; 137) %, р=0,004 and 99 (87; 119) vs 106 (89; 135) %, p=0,002 respectively. While for the 505G/A, the carriers of the rare allele (505A) was associated with higher TAFI levels – 113 (94; 143) vs 106 (89; 132) %, p=0,067. During 18 months of anticoagulant therapy, the frequency of DVT recurrences was 17%, and the frequency of hemorrhagic complications was 30% (major bleedings – 2%, minor bleedings – 28%). There were no PE recurrences. We found no associations among all TAFI genetic variants and the risk of DVT recurrences and hemorrhagic complications during 18 months of anticoagulant therapy.
Conclusion. In pts with venous thromboembolism in Russian population, the –438G/A, 505G/A and 1040C/T polymorphisms of the TAFI gene associate with TAFI levels but do not influence on the risk of DVT recurrences and hemorrhagic complications during 18 months of anticoagulant therapy.
Measurement of TAFI levels
TAFI levels were measured at baseline by a chromogenic assay with reagent kits «STA STACHROM TAFI» (Diagnostica Stago).
Reference values of TAFI levels are 108 ± 25% (according to the manufacturer).
Genetic analysis
Three TAFI genetic polymorphisms (-438G/A, 505G/A and 1040C/T) were investigated.
Genotyping of the 1040C/T polymorphism was performed by PCR - restriction fragment length polymorphism.
Genotyping of the -438G/A and 505G/A polymorphisms was performed using allele-specific PCR.
Statistical analysis
Statistical analysis was performed using a commercially available statistical package (SPSS 17.0 for Windows, SPSS Inc., USA).
The data are presented as a median and interquartile range.
Linear regression was used to estimate the effect of TAFI genetic variants on TAFI levels.
Univariate Cox regression was used to calculate the hazard ratio and 95% confidence interval for the risk of DVT recurrences and hemorrhagic complications.
Linear regression showed that all three polymorphisms were associated with TAFI levels (Table 2).
For the –438G/A and 1040C/T variants, the carriers of rare alleles (–438A and 1040T) were associated with lower TAFI levels than common alleles (–438G and 1040C).
While for the 505G/A, the carriers of the rare allele (505A) was associated with higher TAFI levels.
During 18 months of anticoagulant therapy, the frequency of DVT recurrences was 17%, and the frequency of hemorrhagic complications was 30% (major bleedings – 2%, minor bleedings – 28%) (Fig. 4).
There were no PE recurrences.
Using Cox regression, we found no associations among all TAFI genetic variants and the risk of DVT recurrences and hemorrhagic complications (Table 3)
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Background
Thrombin activatable fibrinolysis inhibitor (TAFI) is involved in the regulation of the balance between coagulation and fibrinolysis.
TAFI is a zymogen which can be activated by several proteases but the most potent activator is the thrombin/thrombomodulin complex.1
Since activation of TAFI depends on generation of thrombin one may speculate that TAFI may be one of factors determining the efficiency and safety of anticoagulant therapy.
Several studies have reported that TAFI levels may be partly determined genetically but results from these studies are conflicting.2-4
The TAFI gene has been mapped to 13q14.11, spans approximately 48 kb of genomic DNA and is organized in 11 exons separated by 10 introns.4
The influence of TAFI genetic variants on the efficiency and safety of anticoagulant therapy is not yet clear.
Results
Range of TAFI levels was from 50 to 217% (Fig. 2).
Median of TAFI levels was 106 (90 to 133)%.
The distribution of TAFI levels was nonparametric.
Conclusions
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In patients with venous thromboembolism in Russian population, the –438G/A, 505G/A and 1040C/T polymorphisms in the TAFI gene associate with TAFI levels but do not influence on the risk of DVT recurrences and hemorrhagic complications during 18 months of anticoagulant therapy.
Objective
References
The aim of the study was to determine the frequency of the TAFI genetic polymorphisms and theirs effect on TAFI levels, the efficiency and safety of anticoagulant therapy in patients with venous thromboembolism in Russian population.
One hundred and eleven patients (76 men) in the age (mean 54 ± 14) years with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were included in the study (Table 1).
Patients received unfractionated or low molecular weight heparin for at least 5 days followed by long-term warfarin therapy (international normalized ratio 2,0-3,0) (Fig. 1).
The follow-up period was 18 months.
Endpoints were DVT/PE recurrences and hemorrhagic complications.
Bouma B. N., Marx P. F., Mosneir L. O. Meijers J. C. M. Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). Thromb Res 2001; 101:
Henry M., Aubert H., Morange P. E. et al. Identification of polymorphisms in the promoter and 3’ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood 2001; 97:
Brouwers G. J., Vos H. L., Leebeek F. W. G. 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:
Franco R. F., Fagundes M. G., Meijers J. C. 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:
The distribution of the three TAFI genetic variants did not deviate from Hardy-Weinberg equilibrium (Fig. 3).
Because the frequency of homozygous genotypes was low we estimated the association between TAFI levels and allelic variants in the TAFI gene but not genotypes.