DISEASE SUSCEPTIBILITY GENES IN PEDIATRIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME

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Antiphospholipid antibody syndrome (APS) is a thrombotic disorder characterized by the association of thrombosis with antibodies directed against phospholipids. In addition to protein C, protein S, antithrombin III deficiency, and Factor V Leiden mutation, APS constitutes a significant cause of thrombosis in children that is often no recognized by pediatricians. APS exists both as a secondary disorder in association with systemic lupus erythematosus (SLE), and as a primary syndrome in the absence of underlying rheumatic disorders. Antiphospholipid antibodies (aPL) are heterogeneous and can be detected by several different assays. Although the syndrome has received increased attention in the literature in recent years, there are still many unanswered questions regarding antibody detection, antigenic target, diagnosis, pathogenesis, and appropriate clinical management. Furthermore, there are unique issues regarding diagnosis, prognosis, and management in the pediatric population. Class II Major Histocopatibility Complex (MHC) genes encode molecules involved with the discrimination of self and non-self, presentation of antigen for immuneactivation, and modulation of T cell recognition. Class II MHC genes have previously been correlated with disease susceptibility for several rheumatic and non-rheumatic disorders by other investigators. Evidence suggests that Class II MHC associations may exist for the expression of aPL and subsequent development of APS in adults, and has not been studied extensively in children. Not all individuals with circulating aPL subsequently develop APS. And recently, Beta 2-Glycoprotein I has been demonstrated to be important in the detection of aPL from individuals who do develop thromboses. Evidence supports a phospholipid binding role for the fifth domain, and thus polymorphism of this region may be associated with APS. The purpose of this project is to identify disease susceptibility genes which may characterize a subgroup of children at increased risk for the development of thrombosis, and potentially contribute to an increased understanding of the pathogenesis of this disorder.