Unraveling the Causal Relationship Between 731 Immunocyte Phenotypes and Asthma Risk: A Bidirectional Mendelian Randomization Analysis

ABSTRACT Growing evidence suggests an association between various immune cell phenotypes and the development of asthma. However, it is still not entirely clear whether specific immune cell phenotypes might causally contribute to the risk of asthma. Despite further studies required to validate this claim, our study delves deeper into explaining this relationship and paving the way toward new therapeutic approaches. Our initial aim is to reveal the causal relationship between 731 immunocyte phenotypes and asthma; a bidirectional Mendelian randomization (MR) analysis was performed. We have investigated 731 immunocyte phenotypes in asthma, using a summary of previously published GWAS. Conducting an MR analysis, we have interpreted the potential causative relationship between them. Our analytical approaches included inverse variance‐weighted average, weighted median (WM) modeling, and pattern‐based approaches. To ensure the robustness and accuracy of our findings, we conducted sensitivity analyses employing MR‐PRESSO, Cochran's Q test, leave‐one‐out, and MR‐Egger approaches. Additionally, we conducted a reverse MR analysis to examine potential reverse causality. Our study revealed 43 immunophenotypes with a causal connection to asthma risk. Following Bonferroni correction and sensitivity analysis, we have identified four immunophenotypes with strong causal associations and reliability, them being: HLA DR on DC (95% CI: 1.0008–1.0014, p = 4.26 × 10 −6 , FDR = 2.21 × 10 −8 ), CD8 on CD28− CD8br (95% CI: 1.0007–1.0020, p = 4.01 × 10 −5 ，FDR = 5.70 × 10 −4 ), CD62L on monocyte (95% CI: 0.9985–0.9995， p = 1.06 × 10 −4 ，FDR = 9.20 × 10 −4 ), CD8br% leukocyte (95% CI: 1.0006–1.0019， p = 1.07 × 10 −4 ，FDR = 1.14 × 10 −3 ). We have confirmed the large co‐inheritance of all these immunophenotypes, which suggests a contribution to asthma development. In addition, reverse MR confirmed that asthma and immune cell phenotypes lack a causal association between them. Our study provides evidence of different immune phenotypes, which are either beneficial or detrimental to asthma. Given the fact that asthma is a broad disease and contains complex immune mechanisms, this research may offer improved outcomes and long‐term asthma treatment strategies.