on January 9, 2003
Published online before print January 9, 2003, doi: 10.1161/01.ATV.0000055740.22563.C5
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Submitted on July 1, 2002
Accepted on December 19, 2002
A Quantitative Trait Locus Influencing Free Plasma Protein S Levels on Human Chromosome 1q. Results From the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project
Laura Almasy *;
From the Department of Genetics (L.A., W.H.S., J.B.), Southwest Foundation, San Antonio, Tex; Unitat d'Hemostasia i Trombosi Departament d'Hematologia (J.M.S., J.C.S., I.C., J.M., M.B., J.F.), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centre National de Genotypage (D.B., A.F., M.L.), Evry, France; and Centre de Genetica Medica i Molecular (X.M., N.S.), Institut de Recerca Oncologica, L'Hospitalet de Llobregat, Barcelona, Spain.
* To whom correspondence should be addressed. E-mail: almasy{at}darwin.sfbr.org.
Objective--Protein S (PS) is a component of the protein C anticoagulant system. PS deficiency is associated with myocardial infarction and venous thromboembolism, two highly prevalent causes of death in industrialized nations. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, we conducted a genome-wide linkage screen to localize genes influencing variation in free PS (fPS) plasma levels.
Methods and Results--fPS levels were measured in 397 individuals in 21 Spanish families. A total of 363 highly informative microsatellite markers were genotyped to provide a 10-cmol/L genetic map, and variance component linkage methods were used. A region on chromosome 1q32, flanked by markers D1S425 and D1S213, showed strong evidence of linkage with fPS levels (logarithm of odds, 4.07; nominal P=7.5x10-6; genome-wide P=0.0024). This region contains two positional candidate genes, the complement component 4-binding protein 
and 
chains, which encode the principal binding protein for PS. Suggestive evidence for linkage was also observed on chromosomes 11p and 19p.
Conclusions--These results represent one of the first genomic screens for quantitative variation in a component of the hemostatic pathway and provide strong evidence for a locus on chromosome 1q influencing fPS levels.
Key words: protein S • linkage • quantitative trait locus
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