Causal effect of circulating cytokines on MRI markers of cerebral small vessel disease: A mendelian randomization study.

ABSTRACT

BACKGROUND: Previous observational studies have reported the correlation between circulating inflammatory cytokines and cerebral small vessel disease (CSVD). However, the causality of this association is uncertain. This study used Mendelian randomization to investigate the causal effect of circulating inflammatory cytokines on neuroimaging changes in CSVD. METHODS: This study utilized genetic variances of 41 inflammatory cytokines and 3 neuroimaging markers of CSVD from genome-wide association studies to assess the causal effects in a two-sample Mendelian randomization approach. Inverse variance weighted analysis was used as the main analytical method, and sensitivity analysis was used to further validate the robustness of the results. RESULTS: Increased IL-18 was associated with increased white matter hyperintensity (WMH) and mean diffusivity (MD) (ß = 0.034, 95 % CI 0.002, 0.065, P=0.038, ß = 0.157, 95 % CI 0.015, 0.299, P=0.030). However, increased IL-18 was associated with decreased fractional anisotropy (FA) (ß = -0.141, 95 % CI -0.279, -0.002, P=0.047). Increased monocyte chemotactic protein-1(MCP-1) was associated with decreased FA (ß = -0.278, 95 % CI -0.502, -0.054, P=0.015). Increased IL-10 levels and IL-2ra levels were associated with decreased risks of MD (ß = -0.228, 95 % CI -0.448, -0.009, p = 0.041; ß = -0.204, 95 % CI=-0.377, -0.031, p = 0.021). CONCLUSIONS: This study revealed that increased levels of IL-18 and MCP-1 were associated with white matter microstructural injury, and increased levels of IL-10 and IL-2ra were associated with decreased MD.