title: A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease.
abstract: One approach to the identification of genetic loci that influence complex diseases is through the study of quantitative risk factors correlated with disease susceptibility. Factor XII (FXII) plasma levels, a related phenotype correlated with thrombosis, is such a risk factor. We conducted the first genomewide linkage screen to localize genes that influence variation in FXII levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (LOD scores 4.73 and 3.53, respectively). On chromosome 5, the peak LOD score occurred in the 5q33-5ter region, near the FXII gene. Addition of a 46C/T mutation in the FXII gene increased the multipoint LOD score to 10.21 (P=3.6 x 10(-12)). A bivariate linkage analysis of FXII activity and thrombosis further improved the linkage signal (LOD = 11.73) and provided strong evidence that this quantitative-trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P=.004). Linkage analysis conditional on 46C/T indicated that this mutation alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represent the first direct genetic evidence that a QTL in or near the FXII gene influences both FXII activity and susceptibility to thrombosis and suggest the presence of one or more still unknown functional variants in FXII.
authors.affiliation: Unitat d'Hemostasia i Trombosi, Departament d'Hematologia, 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: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.forename: Delphine
authors.initials: D
authors.lastname: Bacq
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Alexandra
authors.initials: A
authors.lastname: Faure
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Martínez-Marchán
authors.forename: José
authors.initials: J
authors.lastname: Mateo
authors.forename: Montserrat
authors.initials: M
authors.lastname: Borrell
authors.forename: William
authors.initials: W
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: D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D005174:Factor XII / Q000032:analysis* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D009154:Mutation / Q000235:genetics; D019655:Quantitative Trait, Heritable; D013927:Thrombosis / Q000097:blood* / Q000235:genetics*
chemical_list: D005174:Factor XII