LXRA GENE POLYMORPHISMS AND RESPONSE TO FENOFIBRATE

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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. Cardiovascular disease-CVD kills almost 17 million people internationally every year. Evidence indicates that abnormal lipoprotein, cholesterol, levels and inflammation are linked to CVD pathogenesis. Elevated low-density lipoprotein-LDL, triglycerides, and inflammatory markers, and low high-density lipoprotein-HDL levels are risk factors for CVD development and progression. Current pharmacological treatments for prevention include drugs aimed at restoring lipid homeostasis, which also possess ancillary anti-inflammatory properties such as PPAR-a agonists, e.g., fenofibrate. Liver X receptor a-LXRA is a nuclear receptor known to function as a lipid sensor in the human body and serves as a regulator of lipid homeostasis and suppressor of inflammation. The fibrates are known to modulate reverse cholesterol transport and attenuate inflammation via the LXRA receptor. There is a considerable amount of variability in response to these drugs, and contributing factors to this variability are not well understood. Since LXRA is a drug target for the lipid-modulating effects of fibrates, variability in the gene that encodes LXRA, NR1H3, may be an important determinant of the drug response. Fibrates have also been noted to exhibit so-called pleiotropic effects which include reductions in the prototypical inflammatory mediator of atherosclerosis, C-reactive protein-CRP. It is unknown whether genetic polymorphisms impact these pharmacological effects of fibrates. We propose to investigate whether common NR1H3 gene polymorphisms are associated with either the lipid-modifying or anti-inflammatory effect of fibrates. This approach may add to the understanding of atherosclerotic disease as a systemic process and offer insights into variability in drug response to the biologic and clinic effects of fibrates.