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

Abstract

To cite this article: Morange P-E, Saut N, Antoni G, Emmerich J, Tré gouë t D-A. Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels. J Thromb Haemost 2011; 9: 229-31.Through a genome-wide association study (GWAS), seven new single nucleotide polymorphisms (SNPs) were recently found to be associated with plasma levels of factor (F) VIII and von Willebrand Factor (VWF) by the CHARGE consortium [1]. These SNPs were located in five genes that have not previously been suspected to be associated with these protein levels. More specifically, VWF plasma levels were found to be influenced by SNPs located in TC2N (rs10133762), CLEC4M (rs868875), SCARA5 (rs2726953), STAB 2 (rs4981022) and STXBP5 (rs9390459). 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. Their best proxies were rs4981021 (pairwise r 2 = 0.879), rs4276643 (r 2 = 0.884) and rs1884841 (r 2 = 0.961), respectively (Table 1). Among those, only the rs1884841 showed a promising significant association with VT (Table 1) as the rs1884841-T allele was more frequent in cases than in controls (0.498 vs. 0.432, P = 6.45 · 10 )4). 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). Consequently, these last two SNPs were further examined for support of an association with VT in a sample of 594 VT patients and 588 controls part of the FARIVE study [5]. We were not able to confirm th...

Lessons from genome‐wide association studies in venous thrombosis

“…In the MEGA and HVH studies, the rs1039084 serving as a proxy for the STXBP5 rs9390459 was further found associated with VT, the rs1039084‐G allele being associated with decreased risk of the disease, OR approximately 0.90 [38]. A similar trend was observed in the MARTHA study [39] for the rs9390459‐A allele, OR approximately 0.93, but it did not reach statistical significance. This lack of significance could be due to the under‐powered nature of the MARTHA study, which relied on a sample of 1,150 VT cases and 801 controls.…”

“…This lack of significance could be due to the under‐powered nature of the MARTHA study, which relied on a sample of 1,150 VT cases and 801 controls. Conversely, the TC2N rs1884841 serving as a proxy for the rs10133762 was associated with VT in the French GWAS sample, MARTHA and FARIVE [39] while no association was observed in the HVH study [38]. In the three French collections gathering 2163 VT patients and 2617 controls, the rs1884841‐T allele with frequency approximately 0.44 was associated with an increased OR for VT of 1.27, this allele corresponding to that associated with increased VWF levels according to CHARGE results [36].…”

Combined analysis of three genome-wide association studies on vWF and FVIII plasma levels

“…We have recently observed that, among the newly identified vWF and/or FVIII genes by the CHARGE consortium, TC2N could also be associated with VT risk [27]. Therefore we investigated the effect of the SNPs identified in our meta-analysis on the risk of VT. Our working hypothesis was that SNPs associated with increased (decreased, resp.)…”

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…Several other polymorphisms/genes have been proposed as risk factors for VTE but these lack compelling evidence, including robust statistical replication in independent studies, to be definitively claimed as susceptibility variants/genes for the disease. These include the rs2232710 of SERPINA10 , which encodes the Protein Z‐Dependent Protease Inhibitor of coagulation factors Xa and XIa (Folsom et al , ; Gorski et al , ); SERPINE1 rs2227631, influencing circulating plasminogen activator inhibitor‐1 (PAI‐1) levels (Huang et al , ); C4BPB/C4BPA rs3813948, affecting PS associated phenotypes (Buil et al , ); the rs7080536 of the HABP2 gene, encoding factor VII (FVII) activating protease (Ahmad‐Nejad et al , ); HIVEP1 rs169713 with, as yet, no associated intermediate phenotype (Morange et al , ); F13A1 rs5985 (Val34Leu) (Wells et al , ), influencing FXIII activity (Kohler et al , ; Wartiovaara et al , ); APOH rs8178847, associated with thrombin generation (Tang et al , ); genetic variations at the STAB 2 , STX2 and TC2N loci with suggestive impact on VTE risk (Germain et al , ; Morange et al , ; Smith et al , ; Desch et al , ) via their influence on VWF levels (Smith et al , ); and the rs4602861 (Germain et al , ; Klarin et al , ) at the ZFPM2 locus, whose suspected association with VTE could involve platelet count (Gieger et al , ) and vascular endothelial growth factor (Debette et al , ). Some of these associations, if true, could be restricted to some specific ethnic populations.…”