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Ann Rheum Dis. 2019 Aug;78(8):1079-1089. doi: 10.1136/annrheumdis-2018-214379. Epub 2019 Jun 5.

Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity.

Author information

1
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
2
Institute of Genetics and Genomics in Geneva (iG3), University of Geneva Medical School, Geneva, Switzerland.
3
Swiss Institute of Bioinformatics, Geneva, Switzerland.
4
Department of Rheumatology, Clinical Immunology and Allergy, University of Crete, Medical School, Heraklion, Greece.
5
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.
6
Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
7
Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
8
First Department of Pediatrics, Pediatric Immunology and Rheumatology Referral Center, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece.
9
Department of Rheumatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
10
4th Department of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
11
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland Emmanouil.Dermitzakis@unige.ch boumpasd@uoc.gr.
12
Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
13
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece Emmanouil.Dermitzakis@unige.ch boumpasd@uoc.gr.
14
Medical school, University of Cyprus, Nicosia, Cyprus.
#
Contributed equally

Abstract

OBJECTIVES:

Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity.

METHODS:

mRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC).

RESULTS:

SLE has a 'susceptibility signature' present in patients in clinical remission, an 'activity signature' linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a 'severity signature' best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma-cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease-but not low disease activity-and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues.

CONCLUSION:

Specific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.

KEYWORDS:

autoimmunity; disease activity; systemic lupus erythematosus

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