Abstract
ObjectiveTo investigate the causal relationships between inflammatory proteins, iron metabolism, blood/CSF metabolites, and multiple sclerosis (MS) risk using genetic evidence.MethodsWe performed a two-sample, two-step Mendelian randomization (MR) analysis using European-ancestry genome-wide association study data. The exposures comprised 91 inflammatory proteins, while potential mediators included 1091 blood metabolites, 309 metabolite ratios, 233 circulating metabolic traits, and 338 cerebrospinal fluid metabolites. For the outcome, we assessed MS risk using two independent datasets: International Multiple Sclerosis Genetics Consortium (IMSGC) and UK Biobank. Our primary analysis utilized inverse-variance weighted regression. To ensure robust results, we conducted comprehensive sensitivity analyses including MR-Egger, weighted median, MR-PRESSO, and Bayesian Weighted MR approaches to evaluate potential pleiotropy and strengthen causal inference.ResultsWe observed a statistically significant but modest elevation in MS risk associated with interleukin-7 (IL-7; OR = 1.40, 95% CI: 1.07-1.83, p = 0.016) in the IMSGC cohort, with a weaker effect in the UK Biobank (OR = 1.001, 95% CI: 1.000-1.002, p = 0.047). The IL-7 was causally linked to six blood metabolic traits (taurocholenate sulfate, anthranilate, taurodeoxycholate, albumin, sphingomyelin (d18:1/24:1, d18:2/24:0), leucine-to-phosphate ratio), all influencing MS risk. No significant interactions between iron metabolism and inflammatory proteins were found.ConclusionsThis MR study establishes IL-7 as a potential causal risk factor for MS, partially mediated by blood metabolites. The findings prioritize IL-7 and associated metabolic pathways (bile acids/kynurenine) for therapeutic targeting.