This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HMG-CoA reductase inhibitors (statins) have been shown to decrease vascular morbidity and mortality in large trials. Although these trials included a large number of patients, the benefit of statins across a broader patient population is unclear. In fact, while the average patient in primary prevention trials was in the mid-50s, atherosclerotic and inflammatory processes begin in childhood. Consequently, while statin therapy has demonstrable benefits in middle-aged patients, these benefits may be extended to a much larger population that would not be treated with statins based on contemporary practice guidelines. Since atherosclerosis, via inflammation and endothelial dysfunction, begins to develop at early ages, it stands to reason that immunomodulatory statin effects would be beneficial in a subset of individuals before high-risk features become evident (i.e., individuals currently targeted for lifestyle modifications rather than drug therapy). Moreover, the systemic immunomodulatory effects of statins have not been comprehensively characterized. In fact, studies to date have largely looked at anti-inflammatory effects in vitro in vascular wall cells. Thus, we propose to investigate systemic mechanisms of atorvastatin immunomodulation. Based on ongoing clinical trials, study populations such as ours might soon be considered for statin therapy despite average cholesterol levels, making a true primary prevention approach possible. In addition, there is evidence of genetic association with both atherosclerotic pathogenesis and lipid-lowering responses to statin therapy. Furthermore, the anti-inflammatory effects of statins seem to be variable, with roughly 25% of patients failing to demonstrate reductions in key inflammatory markers. Variations in candidate genes have been identified that could plausibly contribute to the variability in desirable effects of atorvastatin and mediate the non-lipid responses to statins, in general. We therefore also propose to study the influence of variations in the endothelial nitric oxide synthase (eNOS) gene, NOS3, on immunological responses to atorvastatin. This gene appears to be important in both endothelial function and inflammation. This pharmacogenetic approach may further add to the understanding of vascular disease as a systemic process and offer insights into variability in drug response.
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