A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism

G. Antoni, P. Morange, Y. Luo, N. Saut, G. Burgos, S. Heath, M. Germain, C. Biron-Andreani, J. Schved, G. Pernod, P. Galan, D. Zelenika, M. Alessi, L. Drouet, S. Visvikis-Siest, P. S. Wells, M. Lathrop, J. Emmerich, D. Tregouet, F. Gagnon

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2671-2679
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

Keywords

  • Factor VIII
  • Genome-wide association studies
  • Linkage
  • Polymorphisms
  • Venous thromboembolism
  • Von Willebrand factor

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