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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-06-1792.
Submitted June 17, 2002
Accepted July 29, 2002
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
Jose Manuel Soria*, Laura Almasy, Joan Carles Souto, Alfonso Buil, Elisabeth Martinez-Sanchez, Jose Mateo, Montserrat Borrell, William H Stone, Mark Lathrop, Jordi Fontcuberta, and John Blangero
Hematology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
Centre National de Genotypage, Evry, France
* Corresponding author; email: jsoria{at}hsp.santpau.es.
Activated Protein C Resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20-60% 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, even after controlling for 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 GAIT (Genetic Analysis of Idiopathic Thrombophilia) 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) (LOD = 4.5, p=3.08x10-5). 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 FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences risk of thrombosis (p=0.0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and FVIII levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.
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