Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension
Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension
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DOI：
10.1111/bph.14364
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发表时间：
2019-06-01
影响因子：
7.3
通讯作者：
Madhur, Meena S.
中科院分区：
文献类型：
--
作者：
Alexander, Matthew R.;Norlander, Allison E.;Madhur, Meena S.
背景和目的单核细胞在高血压中起着关键作用。本研究的目的是使用一种无偏倚的方法，以确定是否高血压患者在常规治疗中表现出改变的单核细胞基因表达谱，并进行选定的基因的验证研究，以确定新的高血压治疗靶点。实验方法下一代RNA测序鉴定了血压正常和高血压个体的小发现队列中的差异表达基因。在多个验证队列中，使用qRT-PCR、回归分析、全表型关联研究和错义多态性的病例对照分析进一步研究了这些基因中的几个与高血压的关联。我们鉴定了60个在高血压单核细胞中显著差异表达的基因，其中许多与IL-1 β相关。这些基因的表达与平均动脉压（MAP）的单因素和多因素回归分析显示，在血压正常和/或高血压个体的MAP显着相关的四个基因。其中，乳铁蛋白（LTF），肽聚糖识别蛋白1和IL-18受体辅助蛋白（IL 18 RAP）在高血压个体的外周血单核细胞中在单独的验证队列中保持显著升高。有趣的是，在一组非裔美国人中，IL 18 RAP表达与MAP相关。此外，LTF中的错义单核苷酸多态性（rs 1126478）的纯合性降低了抗微生物功能并增加了蛋白质水平，高血压患者相对于对照组（比值比1.16）过度代表。结论和意义这些数据表明，高血压个体中单核细胞表现出促炎基因表达增强，并确定IL 18 RAP和LTF是人类高血压的潜在新型介质。这篇文章是高血压免疫靶点主题部分的一部分。要查看本节中的其他文章，请访问
Background and Purpose Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. Experimental Approach Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. Key Results We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1 beta. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). Conclusions and Implications These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. Linked Articles This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit