Protein C levels are regulated by a quantitative trait locus on chromosome 16 - Results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project

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.