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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-06-1792. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1792v1 101/1/163    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Soria, J. M. Articles by Blangero, J. Search for Related Content PubMed PubMed Citation Articles by Soria, J. M. Articles by Blangero, J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2003, Vol. 101, No. 1, pp. 163-167 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY 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 José Manuel Soria, Laura Almasy, Joan Carles Souto, Alfonso Buil, Elisabeth Martínez-Sánchez, José Mateo, Montserrat Borrell, William H. Stone, Mark Lathrop, Jordi Fontcuberta, and John Blangero From the Unitat d'Hemostàsia i Trombosi, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Southwest Foundation for Biomedical Research, San Antonio, TX; and the Centre National de Genotypage, Evry, France. 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 × 105). 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 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P = .0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (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. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Dawood, R. Mountford, R. Farquharson, and S. Quenby Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR Hum. 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[Full Text] [PDF] D. Scanavini, D. Girelli, B. Lunghi, N. Martinelli, C. Legnani, M. Pinotti, G. Palareti, and F. Bernardi Modulation of Factor V Levels in Plasma by Polymorphisms in the C2 Domain Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 200 - 206. [Abstract] [Full Text] [PDF]

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