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Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis
OBJECTIVES: Patients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys. METHODS: We used mRNA-sequencing in effector (spleen) and target (kidneys, brain) tissues from lupus and control mic...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484391/ https://www.ncbi.nlm.nih.gov/pubmed/35906002 http://dx.doi.org/10.1136/annrheumdis-2021-222069 |
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author | Frangou, Eleni Garantziotis, Panagiotis Grigoriou, Maria Banos, Aggelos Nikolopoulos, Dionysis Pieta, Antigone Doumas, Stavros A Fanouriakis, Antonis Hatzioannou, Aikaterini Manolakou, Theodora Alissafi, Themis Verginis, Panayotis Athanasiadis, Emmanouil Dermitzakis, Emmanouil Bertsias, George Filia, Anastasia Boumpas, Dimitrios T |
author_facet | Frangou, Eleni Garantziotis, Panagiotis Grigoriou, Maria Banos, Aggelos Nikolopoulos, Dionysis Pieta, Antigone Doumas, Stavros A Fanouriakis, Antonis Hatzioannou, Aikaterini Manolakou, Theodora Alissafi, Themis Verginis, Panayotis Athanasiadis, Emmanouil Dermitzakis, Emmanouil Bertsias, George Filia, Anastasia Boumpas, Dimitrios T |
author_sort | Frangou, Eleni |
collection | PubMed |
description | OBJECTIVES: Patients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys. METHODS: We used mRNA-sequencing in effector (spleen) and target (kidneys, brain) tissues from lupus and control mice at sequential time points, and in the blood from 367 individuals (261 systemic lupus erythematosus (SLE) patients and 106 healthy individuals). Comparative cross-tissue and cross-species analyses were performed. The human dataset was split into training and validation sets and machine learning was applied to build LN predictive models. RESULTS: In murine SLE, we defined a kidney-specific molecular signature, as well as a molecular signature that underlies transition from preclinical to overt disease and encompasses pathways linked to metabolism, innate immune system and neutrophil degranulation. The murine kidney transcriptome partially mirrors the blood transcriptome of patients with LN with 11 key transcription factors regulating the cross-species active LN molecular signature. Integrated protein-to-protein interaction and drug prediction analyses identified the kinases TRRAP, AKT2, CDK16 and SCYL1 as putative targets of these factors and capable of reversing the LN signature. Using murine kidney-specific genes as disease predictors and machine-learning training of the human RNA-sequencing dataset, we developed and validated a peripheral blood-based algorithm that discriminates LN patients from normal individuals (based on 18 genes) and non-LN SLE patients (based on 20 genes) with excellent sensitivity and specificity (area under the curve range from 0.80 to 0.99). CONCLUSIONS: Machine-learning analysis of a large whole blood RNA-sequencing dataset of SLE patients using human orthologs of mouse kidney-specific genes can be used for early, non-invasive diagnosis and therapeutic targeting of LN. The kidney-specific gene predictors may facilitate prevention and early intervention trials. |
format | Online Article Text |
id | pubmed-9484391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-94843912022-09-20 Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis Frangou, Eleni Garantziotis, Panagiotis Grigoriou, Maria Banos, Aggelos Nikolopoulos, Dionysis Pieta, Antigone Doumas, Stavros A Fanouriakis, Antonis Hatzioannou, Aikaterini Manolakou, Theodora Alissafi, Themis Verginis, Panayotis Athanasiadis, Emmanouil Dermitzakis, Emmanouil Bertsias, George Filia, Anastasia Boumpas, Dimitrios T Ann Rheum Dis Systemic Lupus Erythematosus OBJECTIVES: Patients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys. METHODS: We used mRNA-sequencing in effector (spleen) and target (kidneys, brain) tissues from lupus and control mice at sequential time points, and in the blood from 367 individuals (261 systemic lupus erythematosus (SLE) patients and 106 healthy individuals). Comparative cross-tissue and cross-species analyses were performed. The human dataset was split into training and validation sets and machine learning was applied to build LN predictive models. RESULTS: In murine SLE, we defined a kidney-specific molecular signature, as well as a molecular signature that underlies transition from preclinical to overt disease and encompasses pathways linked to metabolism, innate immune system and neutrophil degranulation. The murine kidney transcriptome partially mirrors the blood transcriptome of patients with LN with 11 key transcription factors regulating the cross-species active LN molecular signature. Integrated protein-to-protein interaction and drug prediction analyses identified the kinases TRRAP, AKT2, CDK16 and SCYL1 as putative targets of these factors and capable of reversing the LN signature. Using murine kidney-specific genes as disease predictors and machine-learning training of the human RNA-sequencing dataset, we developed and validated a peripheral blood-based algorithm that discriminates LN patients from normal individuals (based on 18 genes) and non-LN SLE patients (based on 20 genes) with excellent sensitivity and specificity (area under the curve range from 0.80 to 0.99). CONCLUSIONS: Machine-learning analysis of a large whole blood RNA-sequencing dataset of SLE patients using human orthologs of mouse kidney-specific genes can be used for early, non-invasive diagnosis and therapeutic targeting of LN. The kidney-specific gene predictors may facilitate prevention and early intervention trials. BMJ Publishing Group 2022-10 2022-07-29 /pmc/articles/PMC9484391/ /pubmed/35906002 http://dx.doi.org/10.1136/annrheumdis-2021-222069 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Systemic Lupus Erythematosus Frangou, Eleni Garantziotis, Panagiotis Grigoriou, Maria Banos, Aggelos Nikolopoulos, Dionysis Pieta, Antigone Doumas, Stavros A Fanouriakis, Antonis Hatzioannou, Aikaterini Manolakou, Theodora Alissafi, Themis Verginis, Panayotis Athanasiadis, Emmanouil Dermitzakis, Emmanouil Bertsias, George Filia, Anastasia Boumpas, Dimitrios T Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title | Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title_full | Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title_fullStr | Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title_full_unstemmed | Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title_short | Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
title_sort | cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis |
topic | Systemic Lupus Erythematosus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484391/ https://www.ncbi.nlm.nih.gov/pubmed/35906002 http://dx.doi.org/10.1136/annrheumdis-2021-222069 |
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