The effects of immunomodulatory drugs on cerebral small vessel disease: A mediation Mendelian randomization analysis

Background: There are only a few recognized drug targets for cerebral small vessel disease (CSVD). Though inflammation is increasingly implicated in the development of CSVD, it remains unclear whether immunomodulation could become a therapeutic target. Accordingly, the Mendelian randomization (MR) method was used to assess the genetically proxied impacts of IL6 receptor (IL6R) inhibitor, IL1(3 inhibitor, Tumor necrosis factor (TNF) inhibitor and (3-tubulin inhibitor on CSVD through. Methods: S ingle nucleotide polymorphisms (SNPs) near the IL6R, , IL1/3, , TNFRSF1A and /3-tubulin genes were identified as genetic proxies for immunomodulatory drugs. These SNPs exhibited significant associations with serum C-reactive protein (CRP) levels in a large European genome-wide association study. The causal effects of immunomodulatory drugs on CSVD manifestations and the mediation influence of 731 peripheral blood immune phenotypes linking these drugs to CSVD manifestations were examined using a two-sample two-step MR approach. Results: A total of 9, 18, 4 and 1 SNP were identified to proxy the effects of IL1(3 inhibitor, IL6R inhibitor, TNF inhibitor and (3-tubulin inhibitor, respectively. MR analysis showed a significant causal relationship between IL1(3 inhibition and reduced volume of periventricular white matter hyperintensity (PWMH). IL6R inhibition was associated with a reduced risk of small vessel stroke, decreased axial diffusivity and mean diffusivity. Genetically proxied TNF inhibition may decrease the occurrence of cerebral microbleeds (CMBs) and severe enlarged perivascular spaces located at white matter (WM-EPVS). It could also protect WM integrity, as evidenced by the reduced volumes of PWMH and deep white matter hyperintensity (DWMH). Various peripheral blood immune phenotypes exhibited significant associations with immunomodulatory drugs. Notably, the median fluorescence intensity (MFI) of CD45 on CD8brcells br cells partially mediated the effects of IL1(3 inhibitor on PWMH volume. Indirect effects of TNF inhibition on PWMH and DWMH volume through the MFI of CD127 on CD28- CD8brcells br cells were observed. The effects of TNF inhibition on the occurrence of any CMBs were partially mediated by the MFI of CD45 on natural killer T cells, and the effects of TNF inhibition on the occurrence of lobar CMBs were partially mediated by the MFI of HLA DR on CD33- HLA DR+ + cells. Furthermore, the MFI of HLA DR on CD33- HLA DR+ + cells partially mediated the effects of TNF inhibition on WM-EPVS. Conclusions: IL1(3 inhibitor, IL6R inhibitor and TNF inhibitor were associated with lower burden of CSVD while the activation of certain immune cells such as Tregs and myeloid cells partially mediated their protective effects.