Purpose: The purpose of this study is to understand the molecular basis of inherited antiphospholipid antibody syndromes as well as define the molecular mechanisms underlying the diverse pattern of clinical phenotypes and laboratory findings that have been observed in patients with antiphospholipid antibodies. Methods: We have established a registry of all individuals identified with a positive lupus anticoagulant and/or anticardiolipin antibody at Duke during the last five years. To date, we have identified over 570 patients with antiphospholipid antibodies. These patients are then recruited to participate in the studies described below. In addition, we have also enrolled family members from 39 of these patients, obtaining genomic DNA, plasma, and serum for characterization. Results: [1] To investigate the genetics of primary antiphospholipid antibody syndromes, we have identified 7 multiplex families that met stringent clinical and laboratory criteria for the diagnosis of a familial antiphospholipid antibody syndrome (APS). In these families, 23 out of 94 family members (24.5%) met criteria by either serologic or coagulation defects, or a combination of clinical, serologic and coagulation defects. Segregation studies rejected environmental and autosomal recessive inheritance patterns, and suggested that a dominant or co-dominant model would best fit the observed data in these families. Linkage studies showed independent segregation of APS and markers for several candidate genes. [2] To investigate the molecular basis of the observed clinical heterogeneity in these patients, we are screening patients for additional primary hypercoagulable states and correlating the presence of a second disorder with the occurrence of a thrombotic event. To date, we have screened 99 patients for the presence of three commonly encountered thrombophilic polymorphisms by restriction enzyme analysis of PCR-amplified genomic DNA: factor VR506Q; the 3'-untranslated prothrombin gene (PTG) polymorphism; and the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR). Fifty-eight patients had primary antiphospholipid antibody syndrome (PAPS), 25 had systemic lupus erythematosus (SLE), 6 had other connective tissue disorders (CTD), and 7 were asymptomatic. Seventy-seven patients sustained one or more TE: 53 had venous TE, and 36 had arterial TE (12 had both venous and arterial TE). Fifteen of 58 female patients (25.9%) sustained one or more miscarriages. Eighteen patients had one or more thrombophilic polymorphisms: 8 were heterozygous for factor VR506Q, 3 were heterozygous for the 3' PTG polymorphism, and 9 were homozygous for the MTHFR polymorphism (including 2 who were also heterozygous for factor VR506Q). Eleven of 18 had PAPS (19%), 6 had SLE (24%), and 1 had CTD (16.7%). Sixteen of the 18 patients had sustained a venous and/or arterial TE (p=0.347). Two individuals homozygous for the MTHFR polymorphism had not sustained a TE. The presence of factor VR506Q or the 3' PTG polymorphism were associated with a significantly increased risk for a venous TE (10 of 11 patients; p=0.0095). In contrast, only 5 patients with the MTHFR polymorphism sustained a venous TE, including the 2 who were also heterozygous for factor VR506Q. None of the thrombophilic genotypes, alone or combined, were associated with an increased risk for arterial TE or miscarriage. Significance: The significance of these studies is that we will understand the genetics of an inherited autoimmune disorder as well as the molecular basis of the phenotypic heterogeneity observed in these patients. This will enable us to better identify patients at risk for developing a thromboembolic complication due to the presence of these antibodies. By defining which patients are at risk, we will be able to develop better therapeutic agents to prevent recurrent complications in these patients and also develop new clinical laboratory assays in order to better monitor their therapy.
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