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

Abstract

Factor VIII (FVIII) and von Willebrand factor (VWF) are two known quantitative risk factors for venous thromboembolism (VTE). To identify new loci that could contribute to VTE susceptibility and to modulating FVIII and/or VWF levels. 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. 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). The BAI3 locus where the rs9363864 maps is a new candidate for VTE risk.