Identification of CD209 as an Intervention Target for Type 2 Diabetes after COVID-19 Infection: Insights from Proteome-wide Mendelian Randomization

Increasing evidence suggests that individuals infected with Coronavirus disease 2019 (COVID-19) are at a higher risk of developing type 2 diabetes (T2D) compared to those who are not infected. However, the mechanisms underlying this relationship remain poorly understood. In this study, we aimed to systematically evaluate the mediating roles of 3,283 plasma proteins in the link between COVID-19 susceptibility and T2D by conducting proteome-wide Mendelian randomization (MR) analyses. Reverse MR, validation in independent datasets, and colocalization analyses were conducted to verify the robustness of the MR results. Furthermore, mediation analysis was carried out to quantify the mediating effects. MR analyses between protein and T2D-related phenotypes were conducted to enhance the comprehension of potential mechanisms. Finally, the druggability of the identified proteins was evaluated. Four proteins causally associated with susceptibility to COVID-19 (ABO, CD209, CUZD1, and QXOS2) exhibited significant causal links with T2D. The protein CD209, which exhibited significant associations in validation and colocalization analyses, was identified as the causal mediating protein. Mediation analysis indicated that CD209 significantly mediated the total effect from COVID-19 susceptibility to T2D ( βindirect[95%CI]: 0.083[0.014-0.152], P=0.019). Further MR analyses revealed significant associations between CD209 and hemoglobin A1c, fasting glucose, fasting insulin, and waist-to-hip ratio. Evaluation of druggability demonstrated that CD209 can bind to Alpha-D-mannose and interact with 9 targets of T2D drugs including dipeptidyl peptidase 4 (DPP4). Our findings propose CD209 as a potential intervention target in individuals infected with COVID-19 to prevent T2D, providing novel insights into the pathophysiology linking COVID-19 and T2D.