Anti-cardiolipin antibodies (ACLs) are a type of anti-phospholipid autoantibody directed against the complex of cardiolipin and apolipoprotein H, also known as beta2-glycoprotein I (beta2-GPI). The presence of high titers of these autoantibodies, often found in autoimmune diseases such as systemic lupus erythematosus (SLE), are pathogenic and have been associated with the anti-phospholipid antibody syndrome. Studies have shown an association of ACLs with the develop of coronary vasculitis and coronary artery disease in mouse models of autoimmunity. Moreover, the presence of ACLs has also been associated with alterations of lipoproteins in the MRL/lpr X BALB/cJ intercross mice. Individuals with SLE are at an increased risk for premature coronary artery disease, and ACLs have been suggested as a contributing factor. The mechanism through which they may exert this effect is unknown, but they may contribute through alterations in lipoprotein levels, an important cardiovascular risk factor. Based upon previous results of genetic studies using inbred autoimmune mouse strains, this proposal hypothesizes that ACLs directly contribute to alterations in lipoprotein levels, and that the gene for beta2-GPI contributes to ACL and lipoprotein levels. This hypothesis will be tested by examining the effect of autoimmune background and ACLs on lipoprotein clearance and synthesis rates, and by testing the beta2-GPI locus for linkage to ACL and lipoprotein levels in MRL/lpr X BALB/cJ intercross mice. If evidence for linkage of beta2-GPI to ACL and lipoprotein levels is found, than molecular expression studies on the beta2-GPI gene will be performed. If evidence for linkage of these phenotypes to beta2-GPI is a lacking in the MRL/lpr X BALB/cj intercross mice, then the beta2-GPI locus and the remainder of the genome will be tested for linkage to these phenotypes in the high AL titer producing NZW x BxSB hybrid by performing a QTL analysis on an intercross between the NZW and BxSB(Yaa+) parental strains. The long-term goal of these studies to begin identifying the genetic contributions to ACL development, and how these contributions impact upon lipoprotein metabolism. This is expected to provide greater understanding into the pathogenesis of the accelerated coronary artery disease in patients with SLE.
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