POS0039 MONOCYTE TRANSCRIPTOMICS AND TARGETED PROTEOMICS DEFINE HETEROGENEOUS SUBGROUPS IN WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND SUBCLINICAL ATHEROSCLEROSIS

Background Systemic lupus erythematosus (SLE), a chronic, inflammatory autoimmune disease, predominantly affects women with a 9:1 female:male incidence. Cardiovascular disease (CVD) is a leading cause of mortality in SLE via accelerated atherosclerosis: the build-up of cells and lipids in the vascular wall and the main pathology underlying CVD. Objectives To define molecular profiles of SLE with subclinical atherosclerosis using multi-omics data analysis and clinical data in a well-characterised cohort of CVD-free SLE women. Methods Multi-omics analyses were conducted to explore the molecular signatures of SLE patients with (SLE-P) and without (SLE-NP) subclinical atherosclerosis defined by non-invasive ultrasound scanning of the carotid and femoral arteries. SLE blood CD14+ monocyte transcriptomes were investigated by bulk RNA-sequencing (SLE-P N=13, SLE-NP N=8), and targeted serum cardiometabolic and cardiovascular proteomics (OLINK) were used to explore matched protein expression (SLE-P N=17, SLE-NP N=20) (no difference in disease activity between groups). Bioinformatics approaches, including pathway and disease module enrichment analyses and extended protein-protein interaction networks, further defined molecular profiles of SLE patients with atherosclerosis from patients that remained plaque free. Gene signature-derived interferon (IFN) scores were applied to investigate heterogeneous subgroups within the cohort as a measure of inflammation. Results Distinct monocyte gene and protein expression profiles were identified in SLE and enriched in biological pathways relating to extracellular mechanisms, including purinergic and cytokine signalling. Lipid regulatory mechanisms were enriched in SLE-P, whereas SLE-NP patient’s transcriptome and proteome profiles were defined by pathways relating to inflammation. Specifically, the type-I IFN pathway was exclusively reduced in SLE-P compared to SLE-NP. IFN scores derived from published IFN-responsive gene expression signatures stratified patients into significantly distinct subgroups (high versus low IFN-response, p=0.0001) with 66% (N=14) of patients showing high IFN expression across multiple signatures not associated with age, ethnicity, or disease activity. However, IFN scores did not predict the presence of sub-clinical atherosclerosis and further heterogeneity was revealed with 46% of SLE-P patients showing a low IFN response (N=6). Further, a measure of plaque lipid content (echogenicity) was inversely correlated with IFN score (grey scale median, p=0.03, r=-0.8) which may reflect distinct plaque phenotypes between these subgroups relating to clinical presentation and risk of cardiovascular events. Conclusion Lipid dysregulation is a key mechanism that drives atherosclerosis pathology and genes and proteins relating to lipid metabolism distinguished SLE patients with and without subclinical atherosclerosis. Differences in levels of interferons and other inflammatory molecules may contribute to unique patterns of gene expression between SLE patients. A distinct subset of SLE-P patients showed low interferon expression, which may be suggestive of a dampened immune response in early subclinical CVD. Further elucidating the complexity of lipid dysregulation, inflammation and immune function in atherosclerosis in SLE will help improve patient stratification towards investigating the efficacy of anti-atherosclerotic therapies. Disclosure of Interests None declared