Targeting the Inflammation-Metabolism Axis in MGUS: Causal Roles of CXCL10 Mediated by Blood Metabolites.

BACKGROUND

Inflammatory cytokines have been implicated in monoclonal gammopathy of undetermined significance (MGUS), but their causal mechanisms remain unclear. Metabolites play pivotal roles in plasma cell dysregulation, however, their potential mediation effects between cytokines and MGUS are unexplored. We aimed to elucidate causal relationships between inflammatory cytokines and MGUS and identify metabolite-mediated pathways.

METHODS

Using genome-wide association study (GWAS) summary statistics, we performed bidirectional two-sample Mendelian randomization (MR) to assess causality between 91 inflammatory cytokines and MGUS. A two-step MR approach was employed to investigate metabolite mediation using data from 1400 blood metabolites. Sensitivity analyses addressed pleiotropy and reverse causality (IVs: p < 1 × 10-5, F-statistic > 10).

RESULTS

MR analysis identified CXCL10 (OR = 2.12, 95% CI: 1.06-4.23, p = 0.034) and IL-6 (OR = 3.61, 95% CI: 1.22-10.65, p = 0.020) as causal risk factors for MGUS. We also found Threonate (OR = 2.24, 95% CI: 1.06-4.75, p = 0.035), X-22776 (OR = 3.45, 95% CI: 1.37-8.67, p = 0.009) and glucose to sucrose ratio (OR = 2.89, 95% CI: 1.18-7.07, p = 0.020) were associated with increased MGUS risk, while N-acetylputrescine to (N(1) + N(8))-acetylspermidine ratio (OR = 0.65, 95% CI: 0.43-0.98, p = 0.039) showed protective effects. Mediation analysis revealed 2 metabolites Threonate and X-22776 mediating CXCL10's effect on MGUS. Threonate mediated 11.2% (β = 0.08, p = 0.014) and X-22776 mediated 17.7% (β = 0.13, p = 0.028) of CXCL10's total effect. Sensitivity analyses confirmed robustness (no pleiotropy: MR-Egger intercept p > 0.05; Cochran's Q p > 0.05).

CONCLUSION

This study deeply reveals the mechanism by which inflammatory cytokines affect the pathogenesis of MGUS through metabolite-mediated pathways, providing new potential targets for the early diagnosis and treatment of MGUS. In the future, other inflammatory cytokines and metabolites that may be related to the pathogenesis of MGUS can be further explored, and the interactions and potential mechanisms between them can be further studied to provide a more comprehensive theoretical basis and practical guidance for the prevention and treatment of MGUS.