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SLC44A2 and Venous Thrombosis

Recently, we completed a meta-analysis of genome wide association studies (GWAS) to identify novel venous thromboembolism (VTE) susceptibility genes (Germain et al. Am J Hum Genet. 2015;96:532-42). This strategy led to the identification and replication of SLC44A2 as a new VTE-associated locus, with lead risk alleles associated with odds ratio for disease of 1.21 (p=2.75 x10-15). The lead SNP at the SLC44A2 locus is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury (TRALI). We further showed that this variant did not associate with known haemostatic plasma markers. Thus, SLC44A2 does not belong to conventional pathways for thrombosis and has not been associated to other cardiovascular diseases nor related quantitative biomarkers.
SLC44A2 rs2288904 (A or G) coincides with in an amino acid substitution in the extracellular domain of the Solute Carrier 44 A2 protein (R154 or Q154, respectively) that may trigger antibody formation in carriers of the minor A allele (during pregnancy and exposure to the major G allele variant). Subsequently, these antibodies can trigger TRALI upon plasma transfusion. Neutrophils and endothelial cells are the primary target for antibodies in TRALI. Currently, we have no evidence that antibodies to SLC44A2 are involved in VTE pathophysiology (no association with plasma transfusions, no sex differences detected in GWAS meta-analysis). However, the fact that the SLC44A2 is expressed by two cell types, namely neutrophils and endothelial cells, that are central to the pathophysiology of thrombosis forms a starting point for our aim i.e. to unravel the mechanism underlying the association between SLC44A2 and VTE. We hypothesise that SLC44A2, and variation at amino acid 154, alters functionalities of neutrophils and endothelium relevant to VTE.
As part of a research project sponsored by the Dutch Thrombosis Foundation we will:
1. Determine the role SLC44A2 in endothelial cell and neutrophil biology by in vitro loss-of-function studies (RNAi)
2. Determine the impact of SLC44A2 rs2288904 on neutrophil and endothelial cell characteristics using materials from healthy volunteers.
3. Investigate the role of SLC44A2 in initiation and propagation of experimental VTE using an in vivo model (conditionally) lacking Slc44a2 (collaboration with University of Michigan, USA, Prof Dr. T.E. Carey)
We expect that as part of this project we will i) identify the mechanism underlying the association between SLC44A2 and VTE; ii) yield novel insights in VTE pathophysiology; and iii) provide novel therapeutic perspectives i.e.  VTE treatment without bleeding as a side-effect.

Furthermore, as part of a related-research project sponsored by the Landsteiner Foundation for Blood Transfusion (LSBR) we will further detail the function of SLC44A2 in venous thrombosis also in the context transfusion-related acute lung injury. Here we will focus on Von Willebrand Factor (VWF), a factor important to hemostasis and expressed on the endothelium, and shown to interact with SLC44A2 in a setting of TRALI. These studies are performed in close collaboration with The University of Giessen, Germany, Dr. B. Bayat).