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Arteriosclerosis, Thrombosis, and Vascular Biology
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on May 13, 2004

Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print May 13, 2004, doi: 10.1161/01.ATV.0000132408.13064.09
A more recent version of this article appeared on July 1, 2004
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Submitted on March 9, 2004
Accepted on April 18, 2004

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 ; and 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; Department of Genetics (L.A., J.B.), Southwest Foundation for Biomedical Research, San Antonio, Tex; Centre National de Genotypage (M.L.), Évry, France.

* To whom correspondence should be addressed. 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.
Key words: protein C • linkage analysis • variance components • NQO1 gene • quantitative trait locus






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