Abstract

The overall objective of the Genetic Analysis of Idiopathic Thrombosis (GAIT) project is to identify genetic -influences on susceptibility to thrombosis through genetic analysis of quantitative risk factors related to disease, including plasma levels of components of the hemostatic and fibrinolytic pathways as well as functional measures of protein activity and blood clotting efficiency. The GAIT sample includes 396 individuals in 21 multigenerational Spanish families for whom quantitative and diagnostic phenotypes are available as well as genotypes for a 10 cM genome scan. Analyses in the GAIT sample have previously documented the strong heritabilities of many of the quantitative measures of hemostasis and fibrinolysis, identified which of these risk factors share pleiotropic genetic influences with liability to thrombosis, and localized quantitative trait loci (QTLs) influencing some of these traits. In this grant application, we propose to follow-up three of the most promising linkage results from the full genome screen using a combination of standard fine-mapping techniques, joint analyses of linkage and linkage disequilibrium, and a newly developed method, called quantitative trait nucleotide analysis, to evaluate positional candidate genes within regions of linkage. The three linkage signals to be pursued include two QTLs for plasma levels of factor XII, one on chromosome 5q with a LOD score of 10.21 and one on chromosome lop with a LOD core of 3.53, and a QTL for tissue factor pathway inhibitor on chromosome 2q (LOD score = 3.52).
The specific aims of the proposed research are: 1) to determine whether the factor XII structural gene (FXJ1) is the previously detected QTL on chromosome 5 influencing plasma levels of factor XII; 2) to determine whether the tissue factor pathway inhibitor structural gene (TFPI) is the previously detected QTL on chromosome 2 influencing plasma levels of TFPI; and 3) to refine and confirm a linkage signal for plasma levels of factor XII on chromosome 10 in a region containing no known positional candidate genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070751-02
Application #
6608055
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Hasan, Ahmed AK
Project Start
2002-07-15
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$442,524
Indirect Cost

  Institution

Name
Southwest Foundation for Biomedical Research
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245

  Publications

Athanasiadis, Georgios; Buil, Alfonso; Souto, Juan Carlos et al. (2011) A genome-wide association study of the Protein C anticoagulant pathway. PLoS One 6:e29168
Calafell, Francesc; Almasy, Laura; Sabater-Lleal, Maria et al. (2010) Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels. Hum Mol Genet 19:517-25
Vila, Luis; Martinez-Perez, Angel; Camacho, Mercedes et al. (2010) Heritability of thromboxane A2 and prostaglandin E2 biosynthetic machinery in a Spanish population. Arterioscler Thromb Vasc Biol 30:128-34
Buil, Alfonso; Tregouet, David-Alexandre; Souto, Juan Carlos et al. (2010) C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. Blood 115:4644-50
Sabater-Lleal, Maria; Chillón, Miguel; Mordillo, Carolina et al. (2010) Combined cis-regulator elements as important mechanism affecting FXII plasma levels. Thromb Res 125:e55-60
Almasy, Laura; Blangero, John (2010) Variance component methods for analysis of complex phenotypes. Cold Spring Harb Protoc 2010:pdb.top77
Almasy, Laura; Blangero, John (2009) Human QTL linkage mapping. Genetica 136:333-40
Viel, Kevin R; Ameri, Afshin; Abshire, Thomas C et al. (2009) Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 360:1618-27
Soria, José Manuel; Almasy, Laura; Souto, Juan Carlos et al. (2009) The F7 gene and clotting factor VII levels: dissection of a human quantitative trait locus. 2005. Hum Biol 81:853-67
Mälarstig, Anders; Buil, Alfonso; Souto, Juan Carolos et al. (2009) Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study. Blood 114:1417-22

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