A genome-wide exploration suggests an oligogenic model of inheritance for the TAFI activity and its antigen levels |
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Authors: | Maria Sabater-Lleal Alfonso Buil Juan Carlos Souto Laura Alamsy Montserrat Borrell Mark Lathrop John Blangero Jordi Fontcuberta José Manuel Soria |
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Institution: | (1) Unitat d’Hemostàsia i Trombosi, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni M.Claret 167. 08025, Barcelona, Spain;(2) Unit of Genomics of Complex Diseases, Research Institute of Hospital de la Santa Creu i Sant Pau, C/Sant Antoni M.Claret 167. 08025, Barcelona, Spain;(3) Department of Population Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA;(4) Centre National du Genotypage, Paris, France |
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Abstract: | Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a protein that potently attenuates fibrinolysis. A considerable proportion
of its variability levels is genetically determined. It has been associated with arterial and venous thrombosis. We conducted
a Genome Wide Scan for genes affecting variation in plasma TAFI levels in 398 subjects from 21 extended Spanish families.
The data were analyzed by a variance-component linkage method. A strong linkage signal was found on the long arm of Chromosome
13, near the DNA marker D13S156, where the structural gene encoding for TAFI is located. In addition, other new linkage signals
were detected on chromosome regions 5p and 7q. More importantly, we performed another multipoint linkage analysis of functional
TAFI conditioned on TAFI antigen levels. We detected a strong linkage signal on Chromosome 19 (LOD = 3.0, P = 0.0001) suggesting a novel QTL in this region involved in the specific functional activity of TAFI, regardless of the TAFI
antigen levels. One notable aspect of this study is the identification of new QTLs that reveal a clearer picture of the genetic
determinants responsible for variation in TAFI levels. Another is the replication of the linkage signal of the CPB2 gene, which confirms an important genetic determinant for TAFI antigen levels. These results strongly suggest an oligogenic
mode of inheritance for TAFI, in which CPB2 gene accounts for a proportion of the variation of the phenotype together with other unknown genes that may represent potential
risk factors for thrombotic disease. |
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