Welcome to the 2021 LUPUS CORA Meeting Program Scheduling

Background and Aims

Copy number variation in complement component 4 (C4) genes, C4A and C4B, has previously been associated with SLE. We asked if C4 copy number variation is connected to clinical features of SLE.

Methods

Copy numbers of C4A and C4B genes were determined for 913 SLE patients and 1,016 healthy controls using targeted sequencing (Fig. 1a). Coding variants in C4 genes were analysed, and HLA alleles called. Clinical data was retrieved from medical records.

Results

A low C4A copy number was more prevalent in SLE patients compared with controls (Fig. 1b; p_C4A=2x10^-24), while C4B copy number did not differ (p_C4B=0.09). C4A copy number was not related to any ACR criteria for SLE, but associated with presence of Ro/SSA and La/SSB autoantibodies. Stratifying SLE patients on anti-SSA/SSB autoantibody status showed a dose-response relationship (Fig. 1c), with a C4A copy number of 0 being strongly associated with SLE with autoantibodies against both SSA and SSB (OR=32.5, CI_95%: 15.9-69.7), while a weaker association was found for patients without anti-SSA/SSB autoantibodies (OR=4.0, CI_95%: 2.1-8.0).

The common C4A loss-of-function (LoF) variant rs760602547 was overrepresented in SLE patients with low C4A copy number (Fig. 1d), and lower plasma C4 levels were detected in LoF carriers compared to non-carriers (p_LoF=1x10^-4, n=369). There was a negative correlation between C4A copy number and number of DRB1*03:01 alleles (r =-0.69).

Conclusions

Our data suggest that C4A has an important role in the development of autoantibodies against Ro/SSA and La/SSB, and that patients with low C4A copy number may constitute a defined subset of SLE.

Background and Aims

Systemic Lupus Erythemathosus (SLE) is a prototypic systemic autoimmune disease characterized by a complex aetiology and heterogenous symptomatology. Epigenetics alterations are known to be mediators of the environmental and genetic factors and to impact transcriptional programs. Here, we aim to increase the knowledge of epigenetic alterations in SLE by conducting an epigenome-wide association study in more than 750,000 CpG sites, and by studying their link with genetics, transcription, sex and serological profiles in data from PRECISESADs project.

Methods

DNA methylation data with the Illumina HumanMethylation EPIC BeadChip derived couple with imputed genetic data and RNAseq based 207 SLE patients and 235 healthy controls from PRECISESADS was analysed. We performed an epigenome wide association study in stratified analyses that interrogated the influence of the presence of autoantibodies, the molecular profiles and the sex on the epigenetic associations. We followed up results by conducting methylation quantitative loci analyses (meQTL), cytokine-epigenetic associations and methylation-expression correlations.

Results

Differential methylation was observed at 1200 CpG sites across the genome associated with molecular subtypes of SLE, and in relation with autoantibodies profiles and sex. We discovered novel genetic loci associated with SLE that might exert their risk through DNA methylation changes. We also identified novel meQTL specific to certain immunological contexts.

Conclusions

This study expands the list of CpGs associated with SLE heterogeneity and pathways invovled in SLE. Our findings reveal novel genetic risk variants with regulatory role associated SLE, novel disease-specific meQTLs, and discovers novel biomarkers for different subtypes of SLE as well as new targets for drug discovery.

Background and Aims

Systemic Lupus Erythematosus (SLE) is a complex autoimmune/inflammatory disease. Juvenile-onset (j)SLE affects 15-20% of lupus patients and is characterized by increased organ involvement and damage, and higher need for immune suppressive treatment. Clinical heterogeneity between ethnicities, age groups and individual patients suggest variable pathophysiology. This study aimed at the definition of patient sub-cohorts with “genetic” vs. “classical” SLE to allow individualized care.

Methods

Applying target enrichment and new generation sequencing, jSLE patients (N=348) from the UK JSLE Cohort Study were screened for disease-causing mutations. Findings were integrated with demographic information and clinical datasets, including SLEDAI, pBILAG organ domain and SLICC damage scores.

Results

Approximately 5.5% of jSLE patients carried disease-causing mutations, primarily affecting nucleic acid sensing and metabolism (68%), immune complex clearance (11%), their combination (11%), immune cell signalling (5%) and NFκB signalling (5%). Patients with “genetic SLE” were younger, and exhibited less organ involvement and damage at diagnosis (neuropsychiatric, haematological, gastrointestinal), while neuropsychiatric involvement developed over time. When compared to the remaining cohort, “genetic SLE” associated with anti-dsDNA antibody positivity at diagnosis, and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit which may explain reduced renal and haematological involvement.

Conclusions

Genetic disease accounts for ≥5.5% of jSLE cases. It associates with peri-pubertal onset, and distinct immunological and clinical pictures. As less commonly present after treatment induction, in “genetic SLE”, autoantibodies may be the result of tissue damage. Routine sequencing will allow for patient stratification, risk assessment, and target-directed treatment with reduced toxicity and increased efficacy.