A Quantitative-Trait Locus in the Human Factor XII Gene Influences Both Plasma Factor XII Levels and Susceptibility to Thrombotic Disease

• Published in: American journal of human genetics Vol. 70; no. 3; pp. 567 - 574
• Main Authors: Soria, José Manuel, Almasy, Laura, Souto, Juan Carlos, Bacq, Delphine, Buil, Alfonso, Faure, Alexandra, Martínez-Marchán, Elisabeth, Mateo, José, Borrell, Montserrat, Stone, William, Lathrop, Mark, Fontcuberta, Jordi, Blangero, John
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.03.2002; University of Chicago Press; The American Society of Human Genetics
• Subjects: Biological and medical sciences; chromosome 5; Chromosome Mapping; Chromosomes, Human, Pair 10 - genetics; Chromosomes, Human, Pair 5 - genetics; Factor XII; Factor XII - analysis; Factor XII - genetics; FXII gene; Genetic Predisposition to Disease; Hematologic and hematopoietic diseases; Humans; Lod Score; Medical sciences; Mutation - genetics; Platelet diseases and coagulopathies; Quantitative Trait, Heritable; Thrombosis - blood; Thrombosis - genetics; Human; Linkage; Family study; Pathogenesis; Cardiovascular disease; Genotype; Chromosome B5; Chromosome C10; Genetic determinism; Factor XII; Thrombosis; Biological activity; Vascular disease; Phenotype; Gene; Risk factor; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/339259

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=3.6×10 −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.