TY - JOUR
T1 - The genomic landscape of ANCA-associated vasculitis
T2 - Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus
AU - Banos, Aggelos
AU - Thomas, Konstantinos
AU - Garantziotis, Panagiotis
AU - Filia, Anastasia
AU - Malissovas, Nikolaos
AU - Pieta, Antigone
AU - Nikolakis, Dimitrios
AU - Panagiotopoulos, Alexandros G.
AU - Chalkia, Aglaia
AU - Petras, Dimitrios
AU - Bertsias, George
AU - Boumpas, Dimitrios T.
AU - Vassilopoulos, Dimitrios
N1 - Funding Information: This work was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (agreement no. 742390), by the Greek Rheumatology Society and Professional Association of Rheumatologists (ERE-EPERE), by the Special Account for Research Grants (S.A.R.G.), National and Kapodistrian University of Athens, Athens, Greece (DV, Grants #12085, 12086) and by SYSCID consortium (European Union’s Horizon 2020 research and innovation programme under grant agreement No 733100). The research leading to these results has been co-funded by the European Commission under the H2020 Research Infrastructures contract no. 675121 (project VI-SEEM). Computational time was granted from the VI-SEEM project and the Greek national HPC facility—ARIS under project ID “RNA_LUPUS”. Acknowledgments Funding Information: This work was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (agreement no. 742390), by the Greek Rheumatology Society and Professional Association of Rheumatologists (ERE-EPERE), by the Special Account for Research Grants (S.A.R.G.), National and Kapodistrian University of Athens, Athens, Greece (DV, Grants #12085, 12086) and by SYSCID consortium (European Union’s Horizon 2020 research and innovation programme under grant agreement No 733100). The research leading to these results has been co-funded by the European Commission under the H2020 Research Infrastructures contract no. 675121 (project VI-SEEM). Computational time was granted from the VI-SEEM project and the Greek national HPC facility—ARIS under project ID “RNA_LUPUS”. Publisher Copyright: Copyright © 2023 Banos, Thomas, Garantziotis, Filia, Malissovas, Pieta, Nikolakis, Panagiotopoulos, Chalkia, Petras, Bertsias, Boumpas and Vassilopoulos.
PY - 2023
Y1 - 2023
N2 - Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE). Methods: We performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients. Results: We report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy. Discussion: We conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.
AB - Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE). Methods: We performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients. Results: We report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy. Discussion: We conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.
KW - autoimmune diseases
KW - endotypes of disease
KW - lupus (SLE)
KW - transcriptomics (RNA-seq)
KW - vasculitis
UR - http://www.scopus.com/inward/record.url?scp=85152318864&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2023.1072598
DO - https://doi.org/10.3389/fimmu.2023.1072598
M3 - Article
C2 - 37051253
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1072598
ER -