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Causal effect of circulating cytokines on MRI markers of cerebral small vessel disease: A mendelian randomization
Yang Yang1, Zhichao Yao1, Lirong Huo1
1Central Laboratory, Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing 100038, China.
Insights
This Mendelian randomization study found that higher levels of inflammatory cytokines, including IL-18 and MCP-1, are causally linked to white matter microstructural injury in cerebral small vessel disease (CSVD). Conversely, IL-10 and IL-2ra showed protective effects against mean diffusivity changes.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Observational studies suggest a link between inflammatory cytokines and cerebral small vessel disease (CSVD).
- The causal relationship between these factors remains unclear.
- Mendelian randomization is employed to investigate causality.
Purpose of the Study:
- To determine the causal effect of circulating inflammatory cytokines on neuroimaging markers of CSVD.
- To clarify the role of specific cytokines in the pathogenesis of CSVD.
Main Methods:
- Utilized genetic variants for 41 inflammatory cytokines and 3 CSVD neuroimaging markers from GWAS.
- Employed a two-sample Mendelian randomization approach.
- Inverse variance weighted analysis and sensitivity analyses were performed for robustness.
Main Results:
- Elevated Interleukin-18 (IL-18) levels associated with increased white matter hyperintensity (WMH) and mean diffusivity (MD).
- Increased IL-18 linked to decreased fractional anisotropy (FA), indicating microstructural damage.
- Monocyte chemotactic protein-1 (MCP-1) associated with reduced FA.
- Interleukin-10 (IL-10) and IL-2 receptor alpha (IL-2ra) associated with decreased MD risk.
Conclusions:
- Increased IL-18 and MCP-1 levels causally contribute to white matter microstructural injury in CSVD.
- Increased IL-10 and IL-2ra levels are associated with a reduced risk of MD, suggesting a protective role.
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) (β = 0.034, 95 % CI 0.002, 0.065, P=0.038, β = 0.157, 95 % CI 0.015, 0.299, P=0.030). However, increased IL-18 was associated with decreased fractional anisotropy (FA) (β = -0.141, 95 % CI -0.279, -0.002, P=0.047). Increased monocyte chemotactic protein-1(MCP-1) was associated with decreased FA (β = -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 (β = -0.228, 95 % CI -0.448, -0.009, p = 0.041; β = -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.
