Genetic Variants of Tumor Necrosis Factor Superfamily, Member 4 (TNFSF4), and Risk of Incident Atherothrombosis and Venous Thromboembolism (Molecular Diagnostics and Genetics‪)‬

Vascular inflammation is a key component in the development and progression of cardiovascular disease (CVD)3 and venous thromboembolism (VTE). Understanding of the processes that initiate and maintain inflammation has increased with the characterization of new disease pathways in the adaptive and innate immune systems. One such pathway is the receptor-ligand pair Ox40-Ox40 ligand (Ox40L), which has shown association with atherosclerosis in both mouse and human (1). Interruption of the Ox40-Ox40L pathway attenuates atherogenesis in LDL receptor --deficient mice (2). Ox40L is a 34-kDa glycoprotein belonging to the tumor necrosis superfamily. The expression of Ox40L has been observed in T cells, B lymphocytes, vascular endothelial cells, and importantly, dendritic cells (3-5). Cross-linking of Ox40L with Ox40 provides a T-cell costimulatory signal, resulting in increased proliferation and cytokine production (4, 5). In addition, there is evidence that Ox40L inhibits interleukin (IL)-10 production and suppresses the function of IL-10-producing T cells, which may be a unique function of Ox40L to regulate immunity and tolerance (2). Attributable to the immunoregulatory role of this pathway, interactions between Ox40 and Ox40L have the potential to enhance inflammatory responses in atherosclerotic plaque.