A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism.
Fiche publication
Date publication
décembre 2010
Auteurs
Membres identifiés du Cancéropôle Est :
Dr VISVIKIS Sophie
Tous les auteurs :
Antoni G, Morange PE, Luo Y, Saut N, Burgos G, Heath S, Germain M, Biron-Andreani C, Schved JF, Pernod G, Galan P, Zelenika D, Alessi MC, Drouet L, Visvikis-Siest S, Wells PS, Lathrop M, Emmerich J, Tregouet DA, Gagnon F
Lien Pubmed
Résumé
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.
Référence
J Thromb Haemost. 2010 Dec;8(12):2671-9