Exploring causal correlations between immune cells and diabetic neuropathy: a Mendelian randomization

Circulating immune cells reportedly affect diabetic neuropathy (DN). Although associations have been previously established between numerous biomarkers and diseases, elucidating their causal relationships remains challenging. Mendelian Randomization (MR) could overcome this difficulty by applying genetic instruments to discern causal links. In this study, we conducted bidirectional two-sample MR to address this problem.

We used freely available genome-wide association study summary statistics. We obtained immune cell phenotype-related summary data from a study cohort comprising 3,757 Sardinian individuals that reported data concerning 731 immune cell phenotypes. We obtained DN-related summary data from the FinnGen database and conducted sensitivity analyses. Furthermore, we assessed horizontal pleiotropy using combined MR-Egger and MR-Presso methods. We evaluated heterogeneity using Cochran's Q test and applied False Discovery Rate correction to the findings.

Our MR analysis significantly associated 24 immune cell phenotypes with DN. Specifically, the presence of CD45 on CD66b + + myeloid cells, HLA DR on CD14 + CD16- monocytes, IgD- CD24- %B cells, and CD27 on IgD- CD38br lymphocytes significantly positively correlated with the risk of DN. In contrast, the presence of CD28- DN (CD4-CD8-) %T cells, FSC-A on HLA DR + T cells, and other four T cell types negatively correlated with DN. Finally, we further confirmed the relationship between different immune cell types and DN.

We demonstrated the immunological susceptibility of DN and clarified how immune responses influence the course of DN. These findings might help inform immunological therapy techniques as well as novel targets for DN diagnosis and treatment.