Novel exomic rare variants associated with venous thrombosis

Abstract

Summary Exomic rare variant polymorphisms (c. 300 000) were analysed in the Scripps Venous Thrombosis (VTE) registry (subjects aged <55 years). Besides coagulation factor V (F5) single nucleotide polymorphisms (SNPs), family with sequence similarity 134, member B (FAM134B; rs78314670, Arg127Cys) and myosin heavy chain 8 (MYH8; rs111567318, Glu1838Ala) SNPs were associated with recurrent VTE (n = 34 cases) (false discovery rate‐adjusted P < 0·05). FAM134B (rs78314670) was associated with low plasma levels of anticoagulant glucosylceramide. Analysis of 50 chr17p13.1 MYH rare SNPs (clustered skeletal myosin heavy chain genes) using collapsing methods was associated with recurrent VTE (P = 2·70 ×10−16). When intravenously injected, skeletal muscle myosin was pro‐coagulant in a haemophilia mouse tail bleeding model. Thus, FAM134B and MYH genetic variants are plausibly linked to VTE risk.

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

“…After 5 minutes, quenching was made with EDTA (10 mmol/L, final) and thrombin formation was quantified. For all studies described in this figure, as for our published studies, [13][14][15][16]24,25 the SkM or CM preparation was dissolved in water and then immediately dialyzed into Tris buffer (pH 7.4) containing 0.6 mol/L NaCl at 4°C. After dialysis, particles causing turbidity were removed by high-speed centrifugation (21 130g for 1 minute), which removed visible aggregates activity for SkM's enhancement of prothrombin activation ( Figure 3D), and DG-FXa still binds to SkM.…”

“…When rare variants in chr17p13.1 MYH genes (clustered skeletal muscle myosin [SkM] heavy chain genes 12 ) were analyzed using collapsing methods, the results suggested their association with recurrent VTE (P = 2.70 × 10 −16 ). 13 This suggested association of recurrent VTE with rare variants in SkM genes led us to hypothesize that SkM is a potentially physiologic and/or pathologic procoagulant factor.…”

Skeletal muscle myosin and cardiac myosin attenuate heparin's antithrombin‐dependent anticoagulant activity

“…Recently, SkM rare exomic variations were identified as associated with increased venous thrombosis risk through a rare exomic variant genotyping study 7,8 . SkM and CM were shown to exert procoagulant effects by binding factor (F) Xa and FVa, thereby forming a surface for the assembly of the prothrombinase complex 1,6 .…”

“…Research on the role of some striated muscle myosins, namely skeletal muscle myosin (SkM) and cardiac myosin (CM), in the pathophysiology of blood coagulation is a promising new area. [1][2][3][4][5][6][7][8] Structurally, SkM and CM are similar and exist as dimers of heterotrimers and consist of six polypeptide chains: two heavy chains, and two pairs of two light chains (essential light chain and regulatory light chain). 3, [8][9][10] Recently, SkM rare exomic variations were identified as associated with increased venous thrombosis risk through a rare exomic variant genotyping study.…”

“…3, [8][9][10] Recently, SkM rare exomic variations were identified as associated with increased venous thrombosis risk through a rare exomic variant genotyping study. 7,8 SkM and CM were shown to exert procoagulant effects by binding factor (F) Xa and FVa, thereby forming a surface for the assembly of the prothrombinase complex. 1,6 In addition, SkM was found to enable negative feedback downregulation of thrombin generation by acting as a cofactor for activated protein C's proteolytic inactivation of FVa.…”