Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach

Abstract

Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 ؋ 10 ؊7 . Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE. (Blood. 2009;113: 5298-5303)

ABO in the Context of Blood Transfusion and Beyond

“…It was already known that there was a higher incidence of both arterial and venous thrombotic disease in A, B or AB individuals compared with O group individuals. This has been confirmed by GWAS results showing decreased risk for venous thromboembolism among individuals of O and A 2 groups (Tregouet et al, 2009). …”

Inherited Thrombophilia: Past, Present, and Future Research

“…The second large-scale association analysis was a genome wide study, including 317,139 SNPs (Tregouet et al, 2009). These SNPs were genotyped in 453 cases and 1,327 controls and the significant results were replicated in two independent case-control studies.…”

Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

“…The last three genes were also found to be associated with FVIII plasma levels, either through the same SNP (rs9390459 for STXBP5) or via different SNPs (rs9644133 for SCARA5 and rs12229292 for STAB 2). Because high plasma levels of these two proteins are considered risk factors for venous thrombosis (VT) [2-4], we investigated the influence of these SNPs on VT risk using the results of our previously published GWAS on VT (in silico GWAS) and two candidate gene case-control studies, MARTHA and FARIVE, all three based on independent French populations [5].Two of these seven SNPs, rs9390459 and rs9644133, were available in the DNA chip array used in our previous GWAS, but none of them showed any trend of an association with VT risk (Table 1). The five other SNPs identified in CHARGE were not typed in our GWAS but according to the HapMap database, three of them, rs12229292, rs2726953 and rs10133762, were in strong linkage disequilibrium with SNPs available in our GWAS.…”

“…The latest two hit SNPs identified in CHARGE, rs4981022 and rs868875, were not in strong LD with any of the GWAS typed SNPs, with best proxies being rs608773 (r 2 = 0.124) and rs4964629 (r 2 = 0.266), respectively. As a consequence, we decided to genotype the rs1884841 in the MARTHA study composed of 1150 VT patients and 801 healthy individuals [5] for further support of association with VT as well as both SNPs that did not have good proxies in our GWAS, rs4981022 and rs868875. While the rs4981022 did not show any evidence of an association with VT risk in MARTHA, the rs868875-G allele was found to be less frequent in cases than in controls (0.292 vs. 0.338, P = 0.0025) and the rs1884841-T more frequent in cases than in controls (0.487 vs. 0.437, P = 0.0024) ( Table 1).…”

“…The last three genes were also found to be associated with FVIII plasma levels, either through the same SNP (rs9390459 for STXBP5) or via different SNPs (rs9644133 for SCARA5 and rs12229292 for STAB 2). Because high plasma levels of these two proteins are considered risk factors for venous thrombosis (VT) [2][3][4], we investigated the influence of these SNPs on VT risk using the results of our previously published GWAS on VT (in silico GWAS) and two candidate gene case-control studies, MARTHA and FARIVE, all three based on independent French populations [5].…”