Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 8, Issue 12, Pages 2671-2679Publisher
WILEY
DOI: 10.1111/j.1538-7836.2010.04092.x
Keywords
factor VIII; genome-wide association studies; linkage; polymorphisms; venous thromboembolism; von Willebrand factor
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Funding
- Canadian Institutes of Health Research [MOP86466]
- Heart and Stroke Foundation of Canada [T6484]
- Fondation pour la Recherche Medicale
- Program Hospitalier de recherche Clinique
- Fondation de France
- Leducq Foundation
- Program Hospitalier de la Recherche Clinique
- Agence Nationale pour la Recherche [ANR-07-MRAR-021]
- France-Canada Research Fund
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Background: Factor VIII (FVIII) and von Willebrand factor (VWF) are two known quantitative risk factors for venous thromboembolism (VTE). Objectives: To identify new loci that could contribute to VTE susceptibility and to modulating FVIII and/or VWF levels. Patients/Methods: A pedigree linkage analysis was first performed in five extended French-Canadian families, including 253 individuals, to identify genomic regions linked to FVIII or VWF levels. Identified regions were further explored using 'in silico' genome-wide association studies (GWAS) data on VTE (419 patients and 1228 controls), and two independent case-control studies (MARTHA and FARIVE) for VTE, gathering 1166 early-onset patients and 1408 healthy individuals. Single nucleotide polymorphisms (SNPs) associated with VTE risk were further investigated in relation to plasma levels of FVIII and VWF in a cohort of 108 healthy nuclear families. Results: Four main linkage regions were identified, among which the well-characterized ABO locus, the recently identified STAB 2 gene, and a third one, on chromosome 6q13-14, harbouring four non-redundant SNPs, associated with VTE at P < 10(-4) in the GWAS dataset. The association of one of these SNPs, rs9363864, with VTE was further replicated in the MARTHA and FARIVE studies. The rs9363864-AA genotype was associated with a lower risk for VTE (OR = 0.58 [0.42-0.80], P = 0.0005) but mainly in non-carriers of the FV Leiden mutation. This genotype was further found to be associated with the lowest levels of FVIII (P = 0.006) and VWF (P = 0.001). Conclusions: The BAI3 locus where the rs9363864 maps is a new candidate for VTE risk.
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