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.


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.
Buil
Alfonso
A
Unitat d'Hemostàsia i Trombosi, Departament d'Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Soria
José Manuel
JM
Souto
Juan Carlos
JC
Almasy
Laura
L
Lathrop
Mark
M
Blangero
John
J
Fontcuberta
Jordi
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008957:Models, Genetic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000032:analysis*; D020151:Protein C Deficiency / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D040641:Quantitative Trait Loci; D013030:Spain / Q000453:epidemiology; D014812:Vitamin K / Q000502:physiology
D011486:Protein C; D014812:Vitamin K; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human