Genotype-dependent cardiovascular and anti-inflammatory effects of fenofibrate

摘要 使用PPAR-α激动剂，如贝特类，已被提议作为一种策略来预防 2型糖尿病患者的心血管事件(MACE)。然而，临床试验表明， 这些药物在这一人群中的益处不一致。追求个性化的心血管疾病预防方法 在糖尿病中，我们最近发现了一个常见的非编码变体(rs6008845，C/T)，位于 PPARA基因，可以用来区分哪些人更有可能从 非诺贝特优于其他T2D患者。在ACCORD LIPID试验中，rs6008845T/T纯合子经历了 非诺贝特可降低50%的MACE，而在C/T杂合子或 C/C纯合子(交互作用p=3.7x10-4)。我们小组的初步证据表明 Rs6008845的作用机制是增强非诺贝特的抗炎作用，而不是降低甘油三酯。 属性。为响应RFA-HL-17-22而编写的这个R21应用程序的目标就是探索这一点 通过利用NHLBI储存库中的ACCORD样本和数据以及 OLINK蛋白质组平台的多重功能。我们打算研究一组1：3的病例对照 嵌套在ACCORD LIPID中，包括所有有MACE和血清等量储存的T/T参与者(n=80) 在BioLINCC中，以及三倍于(n=240)没有MACE的T/T参与者的样本。 通过这一套，我们将解决以下具体目标：1.表征抗炎 T2D中rs6008845T/T纯合子对非诺贝特的反应。血清样本采集地点： 随机分组后的基线和12个月将检测93个炎症相关的血清蛋白(92 包括在OLINK“炎症”多重面板+趋化因子CTACK中)。非诺贝特的作用，AS 与安慰剂相比，将在单个生物标记物上以及通过监督和 非监督数据简化技术，如层次聚类分析，允许识别 受此治疗影响的多标记物炎症征象。2.估计在何种程度上 抗炎作用有助于非诺贝特对T/T的心血管益处 纯合子。使用目标1中生成的生物标志物数据，我们将使用三角测量技术来 估计可归因于该药物效果的非诺贝特对Mace风险的益处的比例 关于炎症生物标志物，考虑到它们与MACE发生率的关联。了解相关机制 通过非诺贝特预防rs6008845 T等位基因纯合子T2D患者的MACE 将为可能使用这种遗传标记来个性化预防心血管疾病提供进一步的支持 T2D，并将为药物遗传学临床试验铺平道路，在临床试验中，随机选择贝特明或 安慰剂按rs6008845基因分层。重要的是，它还将指向路径中的关键节点 在T2D和CVD之间，可以有针对性地开发新的药物来预防这一人群中的Mace。

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.