The Genetic Interface of Immunity and COVID-19: Insights from a Two-Sample Mendelian Randomization Approach

Abstract

Abstract Introduction Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global public health emergency since late 2019. Immune cells are crucial for host defense against viral infection and disease progression. However, the specific immune cell characteristics that influence susceptibility to COVID-19 remain unclear. This study aimed to investigate the causal relationship between immune cell signatures and COVID-19 using MR analysis. Materials and Methods This study utilized publicly available genetic datasets from the COVID-19 Host Genetics Initiative and the Blueprint Consortium and applied a two-sample Mendelian randomization approach to examine the association between 731 immune cell signatures and the risk of COVID-19. We included four types of immune signatures: median fluorescence intensity (MFI), relative cell count (RC), absolute cell count (AC), and morphological parameter (MP) data. We used the inverse-variance weighted (IVW) method as the primary analysis and performed several sensitivity analyses to test the robustness of the results. Results Our analysis revealed 30 distinct immune cell characteristics that were directly associated with the risk of COVID-19, including CD4 + regulatory T cells (CD4 + Treg cells), CCR2 + CD14- CD16 + monocytes, CD86 + plasmacytoid DC AC, CCR2 + plasmacytoid DC (CCR2 + pDC), CCR2 + CD62L + plasmacytoid DC (CCR2 + CD62L + pDC), and CD80 + CD62L + plasmacytoid DC (CD80 + pDC). However, among these findings, only the expression of CCR2 on CD14-CD16 + monocytes had a significant impact (P = 0.0249, OR = 1.0427, 95% CI=[1.0053, 1.0814]) on immune cell attributes in the context of COVID-19. Sensitivity analyses confirmed the validity of the IVW results and ruled out the possibility of horizontal pleiotropy. Conclusion Through two-sample Mendelian randomization analysis, we demonstrated a significant causal relationship between specific immune cell characteristics and the risk of COVID-19. These findings provide important genetic evidence for the development of future vaccines and treatment strategies.