Genetics of Antiphospholipid Syndrome

Abstract

Antiphospholipid syndrome (APS) is defined as recurrent arterial and/or venous thrombosis and obstetric complications in the presence of antiphospholipid antibodies (aPL). The possibility of a genetic predisposition to develop antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been examined by family studies and population studies. Similar to many other polygenic autoimmune diseases, human leukocyte antigen associations have been reported. The genetics of β2-glycoprotein I, one of the most representative target antigens of aPL, has been extensively studied. Additional genetic risk factors for the development of thrombosis in patients with aPL have also been discussed. Although the mechanisms and pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial, different genes seem to be involved.The term "antiphospholipid syndrome" has been proposed to describe the association of arterial and venous thrombosis, recurrent fetal loss, and immune thrombocytopenia with a spectrum of autoantibodies directed against cellular phospholipid components. Because of the antigen spesifity of antiphospholipid antibodies (aPL) and the pathophysiology of thrombosis in antiphospholipid syndrome (APS) are heterogeneous and multifactorial, a single scenario can not explain the mechanisms of thrombophilia or pregnancy morbidity in pateints. Investigation of the clinical epidemiology of APS is in its early stages. During the past 20 years, studies of aPL and APS have been made in many countries [1][2][3][4][5][6][7][8][9][10][11]. aPL appear to occur in all populations studied, with some variations noted in their frequency and in the clinical complications [1,9,10,12,13]. Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus interethnic differences in disease patterns may be due to environmental or genetic factors, or both [1,14]. A genetic basis for aPL antibodies was suggested for the first time when a familial clustering of chronic false-positive syphilis test individuals were detected [15]. The first description about aPL showed two pairs of siblings with lupus anticoagulant (LA) [16]. Subsequently, primary APS was described [17] and Cevallos et al. [18] reported the development of primary APS in one woman whose identical twin sister was an asymptomatic carrier of aPL. Relatives of patients with sistemic lupus erythematosus (SLE) or primary APS had a higher incidence of anticardiolipin antibodies (aCL) [19,20] suggesting that a genetic factor may relevant with aPL. Mackie et al. [21] reported three families having more than one member with LA and called familial lupus anticoagulants. The identification of several pedigrees with an increased frequency of aPL antibodies and the associated clinical manifestations further support the familial form of APS. In one of these studies, a large kindred in which nine individuals had aPL antibodies was described. Associated clinical manifestations included stroke, deep ve...