A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease.
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.
Soria
José Manuel
JM
Unitat d'Hemostasia i Trombosi, Departament d'Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. jsoria@hsp.santpau.es
Almasy
Laura
L
Souto
Juan Carlos
JC
Bacq
Delphine
D
Buil
Alfonso
A
Faure
Alexandra
A
Martínez-Marchán
Elisabeth
E
Mateo
José
J
Borrell
Montserrat
M
Stone
William
W
Lathrop
Mark
M
Fontcuberta
Jordi
J
Blangero
John
J
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*
D005174:Factor XII