Genotype-dependent cardiovascular and anti-inflammatory effects of fenofibrate

非诺贝特的基因型依赖性心血管和抗炎作用

• 批准号: 10043522
• 负责人: Alessandro Doria
• 金额: $ 12.68万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043522
• 关键词: Address; Agonist; Aliquot; Alleles; Ancillary Study; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological Assay; Biological Markers; CCL11 gene; CCL27 gene; CCL3 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Clinical Trials; Cluster Analysis; Complications of Diabetes Mellitus; Data; Data Set; Development; Diabetes Mellitus; Dyslipidemias; Energy Metabolism; Eotaxin; Etiology; Event; Fenofibrate; Fibrates; Genes; Genetic Markers; Genetic Polymorphism; Genotype; Goals; Heterozygote; High Density Lipoprotein Cholesterol; Homeostasis; Homozygote; IL8 gene; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Life Style Modification; Lipids; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PPAR alpha; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Placebos; Plasma; Population; Property; Proteins; Proteomics; Randomized; Recommendation; Research; Risk; Sampling; Serum; Serum Proteins; Supervision; Techniques; Time; Tissues; Triglycerides; Untranslated RNA; Variant; atherogenesis; biobank; cardiovascular disorder prevention; case control; chemokine; cohort; data reduction; data warehouse; experience; genome wide association study; glycemic control; hypertension treatment; improved; inflammatory marker; insight; mortality; novel therapeutics; personalized approach; prevent; repository; response; transcription factor; treatment effect; trend; vascular inflammation

SUMMARY Treatment with PPAR-α agonists such as fibrates has been proposed as a strategy to prevent major cardiovascular events (MACE) in patients with type 2 diabetes (T2D). However, clinical trials have shown inconsistent benefits of these drugs in this population. Pursuing a personalized approach to CVD prevention in diabetes, we have recently identified a common non-coding variant (rs6008845, C/T), flanking the PPARA gene, which can be used to distinguish individuals who are more likely to derive benefit from fenofibrate than other T2D patients. In the ACCORD Lipid trial, rs6008845 T/T homozygotes experienced a 50% MACE reduction in response to fenofibrate whereas no benefit was observed in C/T heterozygotes or C/C homozygotes (p for interaction=3.7x10-4). Preliminary evidence from our group suggests that rs6008845 acts by enhancing the anti-inflammatory effects of fenofibrate rather than its triglyceride-lowering properties. The goal of this R21 application, written in response to RFA-HL-17-22, is to explore this hypothesis further by leveraging the ACCORD samples and data banked in the NHLBI repository as well as the multiplexing capabilities of the OLINK proteomic platform. We intend to study a 1:3 case-control set nested in ACCORD Lipid, including all T/T participants who had a MACE (n=80) and serum aliquots stored in BioLINCC, and a sample of three times as many (n=240) T/T participants who did not have a MACE. Through this set, we will address the following Specific Aims: 1. To characterize the anti-inflammatory response to fenofibrate among rs6008845 T/T homozygotes with T2D. Serum samples collected at baseline and 12 months after randomization will be assayed for 93 inflammation-related serum proteins (92 included in the OLINK “Inflammation” multiplex panel + the chemokine CTACK). The effect of fenofibrate, as compared to placebo, will be evaluated on individual biomarkers as well as by means of supervised and unsupervised data reduction techniques, such as hierarchical cluster analysis, allowing the identification of multi-marker inflammatory signatures influenced by this treatment. 2. To estimate the extent to which anti-inflammatory effects contribute to the cardiovascular benefit exerted by fenofibrate on T/T homozygotes. Using the biomarker data generated in Aim 1, we will use triangulation techniques to estimate the proportion of the fenofibrate benefit on MACE risk that can be ascribed to the effect of this drug on inflammatory biomarkers, given their association with MACE incidence. Understanding the mechanisms through which fenofibrate prevents MACE among T2D patients homozygous for the rs6008845 T allele would provide further support for the possible use of this genetic marker to personalize CVD prevention in T2D and would pave the way for pharmacogenetic clinical trials, in which randomization to fibrate or placebo is stratified by rs6008845 genotype. Importantly, it would also point to critical nodes in the path between T2D and CVD that can be targeted to develop new drugs to prevent MACE in this population.

概括 已提出使用 PPAR-α 激动剂（如贝特类药物）治疗作为预防重大疾病的策略。 然而，临床试验表明，2 型糖尿病 (T2D) 患者的心血管事件 (MACE) 较高。 这些药物对该人群的益处不一致。 在糖尿病中，我们最近发现了一种常见的非编码变异（rs6008845，C/T），位于 PPARA 基因，可用于区分更有可能从中受益的个体 在 ACCORD Lipid 试验中，rs6008845 T/T 纯合子经历了非诺贝特比其他 T2D 患者的治疗。 非诺贝特使 MACE 减少 50%，而在 C/T 杂合子或 C/C 纯合子（相互作用 p=3.7x10-4）。 rs6008845 通过增强非诺贝特的抗炎作用而不是降低甘油三酯起作用 此 R21 应用程序是为了响应 RFA-HL-17-22 而编写的，其目标是探索这一点。 通过利用 NHLBI 存储库中存储的 ACCORD 样本和数据进一步假设 OLINK 蛋白质组学平台的多重功能我们打算研究 1:3 病例对照集。 嵌套在 ACCORD Lipid 中，包括所有储存有 MACE (n=80) 和血清等分试样的 T/T 参与者 BioLINCC 中的样本，以及没有 MACE 的 T/T 参与者的三倍样本 (n=240)。 通过本系列，我们将实现以下具体目标： 1. 表征抗炎药 rs6008845 T/T 纯合子中 T2D 血清样本对非诺贝特的反应。 基线和随机化后 12 个月将检测 93 种炎症相关血清蛋白（92 包含在 OLINK“炎症”多重面板 + 趋化因子 CTACK 中，非诺贝特的作用，如 与安慰剂相比，将根据个体生物标志物以及监督和评估的方式进行评估 无监督的数据缩减技术，例如层次聚类分析，可以识别 2. 评估受该治疗影响的多标志物炎症特征。 抗炎作用有助于非诺贝特对 T/T 产生的心血管益处 使用目标 1 中生成的生物标记数据，我们将使用三角测量技术来 估计非诺贝特对 MACE 风险的获益比例可归因于该药物的作用 考虑到炎症生物标志物与 MACE 发生率的相关性，了解其机制。 通过非诺贝特预防 rs6008845 T 等位基因纯合的 T2D 患者的 MACE 将为可能使用该遗传标记来个性化 CVD 预防提供进一步支持 T2D 将为药物遗传学临床试验铺平道路，其中随机化为贝特或 安慰剂按 rs6008845 基因型分层，重要的是，它还指向路径中的关键节点。 可以针对 T2D 和 CVD 之间的差异，开发新药来预防该人群的 MACE。