title: A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.
abstract: Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P = 3.08 x 10(-5)). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P =.0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (FVIII) levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.
authors.affiliation: Unitat d'Hemostàsia i Trombosi, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. jsoria@hsp.santpau.es
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Souto
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Martinez-Sanchez
authors.forename: José
authors.initials: J
authors.lastname: Mateo
authors.forename: Montserrat
authors.initials: M
authors.lastname: Borrell
authors.forename: William H
authors.initials: WH
authors.lastname: Stone
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: John
authors.initials: J
authors.lastname: Blangero
mesh_terms: D020016:Activated Protein C Resistance / Q000453:epidemiology / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D005169:Factor VIII / Q000378:metabolism*; D005192:Family Health; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D010641:Phenotype; D013030:Spain; D013927:Thrombosis / Q000209:etiology / Q000235:genetics*
chemical_list: D005169:Factor VIII