A quantitative trait locus influencing free plasma protein S levels on human chromosome 1q: results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project.
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.


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 alpha and beta 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.
Almasy
Laura
L
Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549, USA. almasy@darwin.sfbr.org
Soria
José Manuel
JM
Souto
Juan Carlos
JC
Coll
Imma
I
Bacq
Delphine
D
Faure
Alexandra
A
Mateo
José
J
Borrell
Montserrat
M
Muñoz
Xavier
X
Sala
Nuria
N
Stone
William H
WH
Lathrop
Mark
M
Fontcuberta
Jordi
J
Blangero
John
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D017293:Protein S / Q000235:genetics* / Q000378:metabolism*; D040641:Quantitative Trait Loci / Q000235:genetics; D012737:Sex Factors; D019851:Thrombophilia / Q000097:blood* / Q000235:genetics* / Q000517:prevention & control
D017293:Protein S