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.
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.
Authors: C Y Vossen; B P Koeleman; S J Hasstedt; I J Nijman; I J Renkens; P W Callas; F R Rosendaal; E G Bovill Journal: J Thromb Haemost Date: 2013-04 Impact factor: 5.824
Authors: A P Reiner; C L Carty; N S Jenny; C Nievergelt; M Cushman; D J Stearns-Kurosawa; S Kurosawa; L H Kuller; L A Lange Journal: J Thromb Haemost Date: 2008-08-01 Impact factor: 5.824
Authors: Georgios Athanasiadis; Alfonso Buil; Juan Carlos Souto; Montserrat Borrell; Sonia López; Angel Martinez-Perez; Mark Lathrop; Jordi Fontcuberta; Laura Almasy; José Manuel Soria Journal: PLoS One Date: 2011-12-28 Impact factor: 3.240