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.

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

“…Linkage mapping was undertaken by means of the PE LMS II fluorescent marker set (ABI Prism, Foster City, CA) with multiplex polymerase chain reaction (PCR) as described. 24 In a few instances, nearby Genethon (Centre National de Genotypage, Evry, France) markers were substituted for LMS II markers to improve robustness of the scan (http://www.cng.fr/). The PCR products were analyzed on the PE 310, PE 377, and PE 3700 automated sequencers, and they were genotyped by means of the PE Genotyper software (ABI Prism).…”

Inherited Thrombophilia: Past, Present, and Future Research

“…The first one was executed in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study (Souto et al, 2000a). The GAIT study consists of 21 extended Spanish pedigrees.…”

“…Several genome scans were performed in the GAIT study. For the first scan 363 microsatellite markers were genotyped (Soria et al, 2002) while 485 microsatellite markers were used in the second scan (Lopez et al, 2008). Later, a scan employing 307,984 SNPs was performed (Buil et al, 2010;Malarstig et al, 2009).…”

“…Later, a scan employing 307,984 SNPs was performed (Buil et al, 2010;Malarstig et al, 2009). The investigators focussed on associations between genetic markers and intermediate phenotypes of VTE, like lipoprotein(a) levels (Lopez et al, 2008), factor XII levels (Soria et al, 2002), total plasma homocysteine (Malarstig et al, 2009), and C4BP plasma levels (Buil et al, 2010). In these studies quantitative trait loci were discovered, but these loci often included the structural gene for the investigated intermediate phenotype.…”

“…As a result, thrombophilia was then suggested to be an oligogenetic disease in which inherited predisposition results from 2 or more mutations in genes involved in blood clotting (Miletich et al, 1993). The heritability of VTE was investigated in family and twin studies resulting in an estimated heritability of 50-60% (Heit et al, 2004;Larsen et al, 2003;Souto et al, 2000a). Heritability was also determined for individual coagulation factors involved in clot formation, like prothrombin (49-57%), factor V (44-62%), and von Willebrand Factor (34-75%) (de Lange et al, 2001;Souto et al, 2000b).…”