Liver X Receptor-Alpha (LXRA) Polymorphisms in Heart Disease and Drug Response

University Of Florida, Gainesville FL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The research proposed in this application would provide potential novel bio-markers to predict response to current cardiovascular pharmacologic agents and genetic predisposition to CVD risk. Liver X receptor Alpha (LXRA) is a nuclear receptors known to function as a lipid sensor in the human body and serves as a regulator of lipid homeostasis and suppressor of inflammation. Hypothesis 1: NR1H3 (The gene that codes for LXRA) polymorphisms are associated with variable lipid-modifying and immunomodulatory effects of fibrates. Specific Aim 1a: Determine if single nucleotide polymorphisms (SNPs) and derived haplotypes in NR1H3 are associated with variability in lipoprotein response to fenofibrate. Specific Aim 1 b: Determine if NR1H3 SNPs/haplotypes are associated with variability in CRP response to fenofibrate. Hypothesis 2: Fenofibrate exhibits broad cellular immunomodulatory effects. Specific Aim 2a: Determine fenofibrateinduced changes in cytokine/chemokine production from leukocyte cultures of fibrate-treated patients (from Hypothesis 1). This aim will determine fenofibrate's effect on major cellular mediators of inflammation (i.e., leukocytes). Specific Aim 2b: Determine fenofibrate's anti-inflammatory effect on the endothelium by measuring cytokine/chemokine production from HUVECs cultured in the presence of fenofibrate. This aim will delineate LXRA-dependent and independent effects as we will culture cells with fenofibrate a LXRA antagonist. Hypothesis 3: NR1H3 polymorphisms are associated with adverse cardiovascular outcomes in patients with hypertension and stable CVD. Specific Aim 3: Determine if NR1H3 SNPs/haplotypes are associated with variable risk of death, myocardial infarction (Ml) or stroke using genetic samples from the INternational VErapamil SR/Trandolapril STudy (INVEST). CVD exacts tremendous clinical, economic, and humanistic tolls worldwide. To decrease CVD burden, efforts must be made to elucidate the mechanisms of CVD drug response variability, identify novel mechanisms of drug action, and determine novel prognostic CVD biomarkers. We address these issues in this pre-doctoral fellowship proposal. The results will make substantial contributions to public health. [unreadable] [unreadable] [unreadable]