Integrated, multicohort analysis reveals unified signature of systemic lupus erythematosus.

Winston A Haynes,Christopher R Bolen,Rong Mao,Gloria Yiu,Erika Bongen,D James Haddon,Avani Khatri,Paul J Utz,Purvesh Khatri,Imelda Balboni,Vivian K Diep

doi:10.1172/jci.insight.122312

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that follows an unpredictable disease course and affects multiple organs and tissues. We performed an integrated, multicohort analysis of 7,471 transcriptomic profiles from 40 independent studies to identify robust gene expression changes associated with SLE. We identified a 93-gene signature (SLE MetaSignature) that is differentially expressed in the blood of patients with SLE compared with healthy volunteers; distinguishes SLE from other autoimmune, inflammatory, and infectious diseases; and persists across diverse tissues and cell types. The SLE MetaSignature correlated significantly with disease activity and other clinical measures of inflammation. We prospectively validated the SLE MetaSignature in an independent cohort of pediatric patients with SLE using a microfluidic quantitative PCR (qPCR) array. We found that 14 of the 93 genes in the SLE MetaSignature were independent of IFN-induced and neutrophil-related transcriptional profiles that have previously been associated with SLE. Pathway analysis revealed dysregulation associated with nucleic acid biosynthesis and immunometabolism in SLE. We further refined a neutropoiesis signature and identified underappreciated transcripts related to immune cells and oxidative stress. In our multicohort, transcriptomic analysis has uncovered underappreciated genes and pathways associated with SLE pathogenesis, with the potential to advance clinical diagnosis, biomarker development, and targeted therapeutics for SLE.

Highlights

Systemic lupus erythematosus (SLE) is a complex, heterogeneous, chronic autoimmune disease that can affect multiple organs and tissues, including the skin, kidneys, joints, lungs, blood, and CNS
In concordance with the previously reported increased severity of disease observed in patients with pediatric SLE (pSLE) compared with adults [27], we found that patients with pSLE had significantly higher SLE MetaScores compared with patients with adult SLE (aSLE) (Figure 3B)
The robustness and reproducibility of the SLE MetaSignature demonstrate its generalizability to diverse patient populations not observed in traditional, single-cohort analyses [14]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a complex, heterogeneous, chronic autoimmune disease that can affect multiple organs and tissues, including the skin, kidneys, joints, lungs, blood, and CNS. In addition to the IFN signature, upregulation of transcripts associated with granulopoiesis and plasmablasts were observed in individuals who have SLE and were found to be associated with disease activity [3, 5]. McKinney et al used gene expression analysis of purified immune cell populations to identify a transcriptional signature in CD8+ T cells that was associated with increased likelihood of SLE disease flare [11].

Methods

Results

Conclusion