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 ؋ 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 IntroductionVenous and arterial thrombosis may be life-threatening events and are of great importance in public health. Very little is known about the relative importance of genetic factors in thrombosis risk in the general population. 1 Recently, as part of the GAIT (Genetic Analysis of Idiopathic Thrombophila) project, we have quantified the genetic contribution to susceptibility to thrombosis and related phenotypes in the Spanish population. 2,3 Of the quantitative risk factors studied, activated protein C resistance (APCR) had the highest heritability (0.71), and it was genetically correlated with thrombosis ( g ϭ Ϫ 0.65; P ϭ 1 ϫ 10 Ϫ6 ), 2,3 indicating that some of the genes that influence quantitative variation in this phenotype also influence susceptibility to thrombosis.APCR is the most prevalent risk factor for thrombosis, 4 accounting for 20% to 60% of familial thrombophilia. 5 A mutation in the F5 gene (factor V Leiden [FVL]) produces a coding change from Arg506 to Gln at the first cleavage site, where APC acts to inactivate FV. As a consequence, this mutation produces a protein that is intrinsically resistant to APC, causing the APCR pathological phenotype. 6 Prevalence of FVL in different European countries ranges between 2% and 6%. 7 Moreover, APCR is a genetic risk factor for thrombosis independent of FVL. 8,9 Therefore, because of its implication in thrombotic disease, there has been a growing interest in studying other genetic factors that are likely to affect thrombosis risk through quantitative variation in this important intermediate phenotype. The APCR phenotype could theoretically result from a variety of other mutations of critical sites in the F5 or F8 genes. However, no mutations of F8 have yet been identified in patients with the APCR phenotype, 10,11 whereas 2 point ...

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