A multiomic analysis to identify drivers of subclinical vascular disease in systemic lupus erythematosus.

ABSTRACT

BACKGROUND: SLE increases cardiovascular disease (CVD) risk, not accounted by traditional risk factors. Characterization of blood immunological signatures that associate with subclinical CVD and predict its progression has been challenging and may help identify subgroups at risk. METHODS: SLE patients (n=77) and healthy controls (HC n=27) underwent assessments of arterial stiffness, vascular wall inflammation and coronary atherosclerosis burden with cardio-ankle vascular index (CAVI), fluorodeoxyglucose-positron emission tomography/CT (TBR), and coronary CT-angiography, respectively. Whole-blood bulk RNA-sequencing was performed in a subset of subjects (HC n=10, SLE n=20). In a partially overlapping subset (HC n=24, SLE n=64), serum inflammatory protein biomarkers were quantified with an Olink platform. RESULTS: CAVI, TBR and noncalcified coronary plaque burden (NCB) were increased in SLE compared to HC. When comparing SLE patients with high CAVI with those with low CAVI or with HCs, there was downregulation of genes in pathways involved in cell cycle, and differentially regulated pathways related to metabolism, respectively. Distinct serum proteins associated with increased CAVI (CCL23, CSF-1, LAP TFG-beta-1, IL33, CD8A and IL-12B), NCB (MCP-4 and Flt3L) and TBR (CD5, IL-1alpha, AXIN1, CST5 and TNFRSF9; P<0.05). CONCLUSIONS: Blood gene expression patterns and serum proteins that associate with worse vascular phenotypes suggest dysregulated immune and metabolic pathways linked to premature CVD. Cytokines and chemokines identified in associations with arterial stiffness, inflammation and NCB in SLE may allow for characterization of new CVD biomarkers in lupus.