LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis
Rationale: Human genome wide association studies (GWAS) have revealed novel genetic loci that are associated with coronary heart disease (CHD). One such locus resides in LNK/SH2B3 which in mice is expressed in hematopoietic cells and suppresses thrombopoietin (TPO) signaling via its receptor MPL. However, the mechanisms underlying the association of LNK snps with CHD are poorly understood.
Objective: To understand the functional effects of LNK snps and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis.
Methods and Results: Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased MPL signaling. In mice hematopoietic LNK deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase IL-3/GM-CSF receptor signaling in bone marrow myeloid progenitors, while in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases MPL signaling and AKT activation, while cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes pro-thrombotic and pro-atherogenic platelet/leukocyte aggregate formation.
Conclusions:LNK (R262W) is a loss of function variant that promotes TPO/MPL signaling, platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.
- Received April 21, 2016.
- Revision received July 13, 2016.
- Accepted July 15, 2016.