Genetically predicted N-acetylisoleucine levels mediate the association between PB/PC% lymphocyte and normal pressure hydrocephalus: A mediation Mendelian randomization study

Normal pressure hydrocephalus (NPH) is defined by a clinical triad of gait disturbances, urinary incontinence, and cognitive decline. The mechanisms underlying NPH are complex, and emerging evidence suggests that immune cells significantly contribute to the neuroinflammatory processes associated with this condition. However, research elucidating the causal relationships and mechanisms between them remains limited. A mediation Mendelian randomization (MR) was employed to investigate the causal relationship among immune cell phenotypes, NPH, and potential mediating plasma metabolite levels. Using publicly available data from genome-wide association studies, we explored 731 immune cell phenotypes, 1400 plasma metabolite levels, and NPH through a 2-sample MR approach. Furthermore, we employed a mediation MR approach to evaluate the mediating effect of plasma metabolite levels on the relationship between immune cell phenotypes and NPH. Our analysis identified 6 immune cell phenotypes correlated with NPH, with 3 acting as protective factors and 3 as risk factors, none of which showed an inverse causal relationship with NPH. Additionally, we established a causal association between 17 plasma metabolite levels and NPH. Among the 12 identified metabolites, 6 were classified as protective factors and 6 as risk factors. Mediation MR analysis revealed a mediating effect of N-acetylisoleucine levels on the association between plasmablasts/plasma cells% lymphocytes and NPH. Our findings confirm causal relationships linking 6 immune cell phenotypes and 17 plasma metabolite levels to NPH and the protective role of plasmablasts/plasma cells% lymphocytes in NPH through reducing N-acetylisoleucine levels, thereby providing new insights into the pathophysiological mechanisms underlying NPH.