Project #2: SOLVABLE: Study of Lupus Vascular and Bone Longterm Endpoints

Systemic lupus erythematosus (SLE) is the prototypic systemic inflammatory autoimmune disease that affects predominantly young premenopausal women.  As survival has improved over the last two decades, increasing numbers of young women with SLE are experiencing cardiovascular (CVD) and osteoporotic (OP) related complications typically associated with aging in non-SLE populations of women.  The occurrence of these complications remains increased, even after adjusting for known traditional risk factors and the use of corticosteroids associated with these complications.  Macrophages play a critical role in the initiation and progression of atherosclerosis and monocytes or macrophages are precursors of osteoclasts, which contribute to osteoporosis. Our preliminary data shows during the in vitro differentiation of normal monocytes into macrophages upregulation of a large number of genes important for lipid metabolism and transport, which promote the formation of foam cells, and many genes important for function of osteoclasts, even though these cells are not osteoclasts. The specific aims in 5-year longitudinal study with 180 lupus and 180 non-lupus participants are 1) continue longitudinal followup of study participants at three years and five years after baseline assessment to determine the rate of progression of carotid, coronary, and aortic atherosclerosis in lupus women compared to age- race- and geographically-similar controls, 2) examine lipid metabolism gene expression profiles in macrophages and relate these gene expression profiles to clinical observations of subclinical CVD, and 3) examine gene expression profiles in macrophages which are potentially important in osteoclast function and relate these gene expression profiles to previous clinical observations of bone mineral density, BMD, measured at the lumbar spine and hip. The main goal of this study is to test the hypothesis that the increased occurrence of subclinical and CVD and OP markers and events in women with SLE, are associated with differential gene expression profiles of selected biological pathways or function in macrophages.  Focusing on the macrophage as the key cell involved in the pathophysiology of both CVD and OP and merging the new data on gene upregulation in macrophages with a carefully and extensively defined phenotype, in a longitudinal cohort, should provide new insights into the chronic inflammatory state that predisposes women with lupus to develop accelerated CVD and OP.