Systemic lupus erythematosus (SLE) is the prototypic systemic inflammatory autoimmune disease that affects predominantly younger premenopausal women. Compared to U.S. White women, SLE is 3-4 times more frequent in U.S. Black women. The risk of coronary heart disease (CHD) in SLE women is up to 50 times higher than in the general population. The conventional risk factors are insufficient to explain premature CHD in SLE patients. Compared to about 1-5 percent prevalence of antiphospholipid antibodies (APA) in the general U.S. White population, about 50 percent of the SLE patients are positive for APA. The oxidation of LDL and its involvement in the development of foam cell-laden streaks in the artedal wall is believed to initiate the atheroscterotic process. Several lines of evidence suggest the existence of a relationship between oxidative parameters of LDL and APA in SLE patients. Thus, it seems logical to focus on those gene products that directly or indirectly affect the process of LDL oxidation and the production of APA. The proposed study is focused on a newly identified group of risk genes for CHD known as paraoxonase (PON). The high-density lipoprotein (HDL)-bound PON has been shown to inhibit LDL oxidation and low PON activity is associated with CHD risk. Three PON genes, PON1, PON2 and PON3 are linked on chromosome 7. Common genetic variation in the PON1 gene has been found to affect the extent of LDL oxidation and the risk of CHD in non-SLE patients. Our own studies have confirmed the association of PON1 and PON2 poiymorphisms with CHD in non-SLE patients. Our preliminary data in SLE women show that the PON1 polymorphism is also associated with the occurrence of APA. in this proposal, we intend to test the hypothesis that common genetic variation in the PON gene cluster along with PON activity affects the occurrence of LDL oxidation and APA that eventually lead to high prevalence of CHD in SLE patients. We will systematically screen the three PON genes for new mutations (Aim 1) and, in conjunction with known PON potymorphisms, we will evaluate their genetic and functional significances (Aims 2-4).
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