Genetic insights into the causal linkage between systemic inflammatory regulators and frailty.

OBJECTIVES

Previous studies have suggested the associations between systemic inflammation and the risk of frailty, but causal relationships between them remain not well established. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the causal links between systemic inflammatory regulators and frailty.

METHODS

Genetic variants associated with systemic inflammatory regulators were obtained from a comprehensive genetic study on 41 circulating cytokines, such as interleukin-4 (IL-4), eotaxin, and macrophage inflammatory protein-1β (MIP1β). We integrated summary-level data on frailty from two independent genetic studies on frailty index (FI) and Fried frailty score (FFS). The inverse-variance weighted method was used to assess the causal estimate. Sensitivity and heterogeneity analysis was performed to evaluate the stability of the estimates. The false discovery rate (FDR) method was used for P value adjustment of multiple comparisons.

RESULTS

Genetically elevated levels of MIP1β and decreased levels of eotaxin were suggestively associated with increased FI (MIP1β: β = 0.016, Praw = 0.006, PFDR = 0.083; eotaxin: β = -0.030, Praw = 0.007, PFDR = 0.083) and FFS (MIP1β: β = 0.008, Praw = 0.027, PFDR = 0.247; eotaxin: β = -0.015, Praw = 0.014, PFDR = 0.247). In contrast, genetically predicted FI was suggestively associated with decreased levels of IL-4 (β = -0.395, Praw = 0.040, PFDR = 0.638) and platelet-derived growth factor BB (PDGF-BB, β = -0.385, Praw = 0.047, PFDR = 0.638) and increased levels of stem cell factor (SCF, β = 0.527, Praw = 0.005, PFDR = 0.204). Similar results were obtained from different sensitivity analysis.

CONCLUSIONS

The present study demonstrates that increased MIP-1β levels and decreased eotaxin levels might lead to a higher risk of frailty, whereas frailty might reduce the levels of IL-4 and PDGF-BB and increase the levels of SCF.