Abstract Background and aims Interferon-alpha (IFN-a) are potent proinflammatory cytokines involved in antiviral responses. Preclinical evidence suggests that IFN-a are key mediators of inflammation in atherosclerosis, yet observational data remains scarce as conventional immunoassays are too insensitive to reliably quantify their very low circulating concentrations. Methods We conducted a nested case-control study of 375 randomly selected Generation Scotland participants with a first incident ischaemics stroke (IS), matched 1:1 to controls by age and sex. IFN-a levels were measured by ultra-sensitive digital ELISA on a fully automated Simoa HD-X platform using serum collected a median of 8.4 years before IS. Associations between log-transformed IFN-a concentrations and IS risk were examined using conditional logistic regressions. Results We included 353 case-control pairs (n=706) with reliable IFN-a measurements (mean age=62.0 years SD=11.8, 50.4% males). The median serum IFN-a concentration was 32.3 fg/mL (Q1-Q3: 21.3-53.5; range: 9.2-8,089.2 fg/mL). Higher log-IFN-a levels were associated with increased IS risk after adjustment for cardiovascular risk factors (per SD increment: OR=1.23; 95% CI: 1.03, 1.48; p=0.025). In secondary analyses, higher point estimates were observed for IS cases defined from hospital admissions but were similar in people with vs without atrial fibrillation or autoimmunity. Conclusions Higher IFN-a levels were associated with an increased long-term risk of IS. These findings demonstrate the value of ultra-sensitive proteomic platforms for stroke biomarker discovery and suggest IFN-a may play a role in stroke pathogenesis. Further studies are needed to determine the mechanisms underlying this association and evaluate the potential of IFN-a as a therapeutic target. Conflict of interest All authors: nothing to disclose.
Rioux et al. (Fri,) studied this question.