LXRA GENE POLYMORPHISMS AND RESPONSE TO FENOFIBRATE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 心血管疾病--全球每年有近1700万人死于心血管疾病。有证据表明，脂蛋白、胆固醇、水平异常和炎症与CVD的发病有关。低密度脂蛋白-低密度脂蛋白、甘油三酯和炎症标志物升高以及低高密度脂蛋白-高密度脂蛋白水平是心血管疾病发生和进展的危险因素。目前预防的药物治疗包括旨在恢复脂质稳态的药物，这些药物还具有辅助抗炎特性，如PPAR-a激动剂，如非诺贝特。 肝X受体α-LXRA是一种核受体，在人体内起着脂质感受器的作用，是脂质稳态的调节者和炎症的抑制者。已知贝特类通过LXRA受体调节胆固醇的反向运输和减轻炎症。对这些药物的反应有相当大的变异性，导致这种变异性的因素还不是很清楚。由于LXRA是贝特类调脂作用的药物靶点，编码LXRA的基因NR1H3的可变性可能是药物反应的一个重要决定因素。贝特类药物也显示出所谓的多效性作用，其中包括减少动脉粥样硬化的典型炎症介质C反应蛋白-C反应蛋白。目前尚不清楚基因多态是否会影响贝特类药物的这些药理作用。我们建议调查常见的NR1H3基因多态性是否与贝特类药物的调脂或抗炎作用有关。这种方法可能会增加对动脉粥样硬化性疾病作为一个系统过程的理解，并提供对贝特类药物生物和临床效应的药物反应的变异性的见解。

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.