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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1321.)
© 2004 American Heart Association, Inc.

Thrombosis

Protein C Levels Are Regulated by a Quantitative Trait Locus on Chromosome 16

Results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project

Alfonso Buil; José Manuel Soria; Juan Carlos Souto; Laura Almasy; Mark Lathrop; John Blangero; Jordi Fontcuberta

From Unitat d‘Hemostàsia i Trombosi (A.B., J.M.S., J.C.S., J.F.), Departament d‘Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; the Department of Genetics (L.A., J.B.), Southwest Foundation for Biomedical Research, San Antonio, Tex; Centre National de Genotypage (M.L.), Évry, France.

Correspondence to Dr Jose Manuel Soria, Unitat d’Hemostàsia i Trombosi, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni M^a Claret 167, 08025, Barcelona, Spain. E-mail jsoria{at}hsp.santpau.es

Objective— Protein C (PC) is a component of the protein C anticoagulant pathway. PC deficiency is a risk factor associated with venous thromboembolism. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, we conducted a genome-wide linkage scan to localize genes that influence variation in PC plasma levels.

Methods and Results— PC levels were measured in 398 individuals belonging to 21 Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1-cM genetic map. Variance component linkage methods were used to evaluate linkage and to detect quantitative trait loci (QTL). A region on chromosome 16 (16q23), flanked by markers D16S3106 and D16S516, showed strong evidence of linkage with PC levels (LOD=3.69). This region contains 1 positional candidate gene, the NAD(P)H:dehydrogenase quinone 1 (NQO1), involved in vitamin K metabolism. The association of 1 SNP of this gene with PC levels (P=0.005) strongly supports the implication of NQO1 gene in the variability of PC levels.

Conclusions— These results illustrate the application of genomic scans to identify the genetic determinants of quantitative variation in a component of the hemostatic pathways. They provide strong evidence for a locus (QTL) on chromosome 16 that influences PC levels.

As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, we conducted a genome-wide linkage scan to localize genes influencing variation in PC plasma levels. Our results provide strong evidence for a locus (QTL) on chromosome 16. This locus is likely the NQO1 gene that influences PC levels.

Key Words: protein C • linkage analysis • variance components • NQO1 gene • quantitative trait locus