Author:
Garantziotis Panagiotis,Nikolakis Dimitrios,Doumas Stavros,Frangou Eleni,Sentis George,Filia Anastasia,Fanouriakis Antonis,Bertsias George,Boumpas Dimitrios T.
Abstract
ObjectivesTreatment of Systemic Lupus Erythematosus (SLE) is characterized by a largely empirical approach and relative paucity of novel compound development. We sought to stratify SLE patients based on their molecular phenotype and identify putative therapeutic compounds for each molecular fingerprint.MethodsBy the use of whole blood RNA-seq data from 120 SLE patients, and in a data-driven, clinically unbiased manner, we established modules of commonly regulated genes (molecular endotypes) and re-stratified patients through hierarchical clustering. Disease activity and severity were assessed using SLEDAI-2K and Lupus Severity Index, respectively. Through an in silico drug prediction pipeline, we investigated drugs currently in use, tested in lupus clinical trials, and listed in the iLINCS prediction databases, for their ability to reverse the gene expression signatures in each molecular endotype. Drug repurposing analysis was also performed to identify perturbagens that counteract group-specific SLE signatures.ResultsMolecular taxonomy identified five lupus endotypes, each characterized by a unique gene module enrichment pattern. Neutrophilic signature group consisted primarily of patients with active lupus nephritis, while the B-cell expression group included patients with constitutional features. Patients with moderate severity and serologic activity exhibited a signature enriched for metabolic processes. Mild disease was distributed in two groups, exhibiting enhanced basic cellular functions, myelopoiesis, and autophagy. Bortezomib was predicted to reverse disturbances in the “neutrophilic” cluster, azathioprine and ixazomib in the “B-cell” cluster, and fostamatinib in the “metabolic” patient subgroup.ConclusionThe clinical spectrum of SLE encompasses distinct molecular endotypes, each defined by unique pathophysiologic aberrancies potentially reversible by distinct compounds.
Subject
Immunology,Immunology and Allergy
Reference55 articles.
1. The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease;Lamb;Science,2006
2. The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations;Keenan;Cell Syst,2018
3. Support for Phosphoinositol 3 Kinase and mTOR Inhibitors as Treatment for Lupus Using in-Silico Drug-Repurposing Analysis;Toro-Domínguez;Arthritis Res Ther,2017
4. Combined Genetic and Transcriptome Analysis of Patients With SLE: Distinct, Targetable Signatures for Susceptibility and Severity;Panousis;Ann Rheum Dis,2019
5. The Systemic LupusActivity Measure-Revised, the Mexican Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and a Modified SLEDAI-2K are Adequate Instruments to Measure Disease Activity in Systemic Lupus Erythematosus;Uribe;J Rheumatol,2004
Cited by
10 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献