153 | Untargeted Serum Proteomics in Patients With Systemic Lupus Erythematosus Reveals Molecular Pathways Associated With Ethnicity and Disease Phenotypes

Aims: We aimed to generate comprehensive serum proteomic profiles in patients with systemic lupus erythematosus (SLE) using untargeted mass spectrometry (MS), and explore associations between individual proteins, protein pathways and SLE clinical phenotypes. Methods: Unbiased quantitative proteomics was performed in 60 SLE patients using serum liquid chromatography-tandem MS. Gene set variation analysis was performed (Hallmark gene set) to quantify protein pathways. Associations between clinical features and protein pathways, as well as individual proteins, were assessed using differential abundance analysis (DA) with linear regression models. Covariates in multivariable regression included age, sex, ethnicity and renal impairment. Results: 23 protein pathways were identified from 1092 proteins quantified in 58 SLE patients (1 end-stage renal failure patient and 1 outlier excluded; median (IQR) age 42 (34–52) years, 91% female, 48% Asian ethnicity, 52% European ethnicity; 48% active disease (SLEDAI-2K > 4)). Using multivariable linear regression, three protein pathways were significantly positively associated with organ damage: Kirsten rat sarcoma viral oncogene homolog (KRAS) signalling up, complement and xenobiotic metabolism. A protein from the complement and KRAS signalling up pathways, Cathepsin S, was significantly positively associated with organ damage. The myogenesis pathway was significantly positively associated with biopsy-proven lupus nephritis (LN). The apoptosis pathway was significantly positively associated with prednisolone use. No individual proteins were associated with biopsy-proven LN or prednisolone use. Two protein pathways were significantly negatively associated with Asian ethnicity using univariable regression only: complement and IL2 STAT 5 signalling. One protein from the complement pathway, fibronectin, was associated with Asian ethnicity. Conclusions: Serum proteomics identified protein pathways associated with organ damage, biopsy-proven LN, prednisolone use and ethnicity in patients with SLE. Corresponding individual proteins from these pathways were associated with organ damage and ethnicity. This highlights the potential for untargeted serum proteomics to advance understanding of SLE pathogenesis and elicit clinically useful biomarkers.