Frailty phenotype, genetic risk and long-term incident systemic lupus erythematosus risk: Insights from the UK Biobank study integrated with multi-omics analysis.

Frailty, a marker of biological ageing and reduced physiological reserve, is linked to many chronic conditions, yet its role in the development of systemic lupus erythematosus (SLE) remains unclear. To examine the association between frailty and incident SLE and to investigate potential inflammatory and genetic mechanisms underlying this relationship. We conducted a prospective cohort study among 462,762 participants from the UK Biobank to examine the associations of physical frailty and frailty index with incident SLE. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, with further analyses assessing the interaction and joint effects of frailty and polygenic risk. Gene-level overlap between frailty and SLE was evaluated using MAGMA. In addition, we integrated circulating inflammatory markers and plasma proteomic profiles to identify potential mediating pathways and candidate biomarkers. During a median follow-up of 13.2 years, 309 of 462,762 participants (0.07%) developed incident SLE. Compared to non-frail individuals, both pre-frail and frail participants had a higher risk of developing SLE, with stronger associations observed in those with higher polygenic risk scores. Gene analysis identified 39 shared genes that were significantly correlated with both frailty and SLE. Circulating inflammatory markers, including C-reactive protein, were found to partially mediate the frailty-SLE relationship. Proteomic analyses identified ANGPTL3, CST3 and TNFSF8 as the candidate risk-related biomarkers associated with future incident SLE. Frailty is associated with an increased long-term risk of incident SLE, particularly in genetically susceptible individuals. Inflammatory cell measures and circulating proteins, including ANGPTL3, CST3 and TNFSF8, may help identify elevated SLE risk in pre-frail and frail populations.