Genotype-dependent cardiovascular and anti-inflammatory effects of fenofibrate

总结 已提出使用PPAR-α激动剂（如贝特类）治疗，作为预防重大 2型糖尿病（T2 D）患者的心血管事件（MACE）。然而，临床试验表明， 这些药物在该人群中的获益不一致。追求个性化的CVD预防方法 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，其可用于区分更可能从以下中获益的个体： 非诺贝特优于其他T2 D患者。在雅阁脂质试验中，rs6008845 T/T纯合子经历了 非诺贝特治疗后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）。我们小组的初步证据表明， rs6008845通过增强非诺贝特的抗炎作用而不是其降低血糖的作用 特性.本R21应用程序是为响应RFA-HL-17-22而编写的，其目的是探索这一点 进一步利用雅阁样本和NHLBI存储库中的数据以及 OLINK蛋白质组学平台的多路复用功能。我们打算研究一个1：3的病例对照组 嵌套在雅阁Lipid中，包括发生MACE的所有T/T受试者（n=80）和储存的血清等分试样 在BioLINCC中，以及三倍于（n=240）未发生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.为了表征抗炎药 在患有T2 D的rs6008845 T/T纯合子中对非诺贝特的应答。采集的血清样本 将对基线和随机分组后12个月的93种炎症相关血清蛋白（92 包括在OLINK“炎症”多重组中+趋化因子CTACK）。非诺贝特的作用， 与安慰剂相比，将对个体生物标志物以及通过监督和 无监督的数据减少技术，如分层聚类分析，允许识别 受此治疗影响的多标记炎症特征。2.为了估计 抗炎作用有助于非诺贝特对T/T产生的心血管益处 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， 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 炎症生物标志物与MACE发生率相关。了解机制 非诺贝特通过其预防rs6008845 T等位基因纯合子T2 D患者的MACE 这将为可能使用这种遗传标记来个性化CVD预防提供进一步的支持， T2 D，并将为药物遗传学临床试验铺平道路，其中随机化贝特或 安慰剂按rs6008845基因型分层。重要的是，它还将指向路径中的关键节点 T2 D和CVD之间的关系，可以有针对性地开发新药，以预防该人群的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.