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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:508.)
© 2003 American Heart Association, Inc.

Thrombosis

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; José Manuel Soria; Juan Carlos Souto; Imma Coll; Delphine Bacq; Alexandra Faure; José Mateo; Montserrat Borrell; Xavier Muñoz; Nuria Sala; William H. Stone; Mark Lathrop; Jordi Fontcuberta; John Blangero

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.

Correspondence to Laura Almasy, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. 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-cM 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 (LOD score, 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 ß 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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