Key result
Mendelian randomization identified 30 immune cells and 8 inflammatory proteins causally associated with COPD, with CXCL10 mediating 14.49% of the effect of CD11c on CD62L+ myeloid dendritic cells.
Why the study?
Observational studies indicate immune cells and circulating inflammatory proteins may play a dual role in COPD progression, but the precise mechanisms remain uncertain.
Do immune cells causally affect COPD risk, and is this effect mediated by circulating inflammatory proteins?
Observational (n=394,244)
Do immune cells causally affect COPD risk, and is this effect mediated by circulating inflammatory proteins?
Mendelian randomization identifies specific immune cells and inflammatory proteins (e.g., CXCL10, IL20RA) that causally mediate the risk of developing COPD, offering potential novel therapeutic targets.
MR links specific immune cells to COPD via partial inflammatory protein mediation; hypothesis-generating, warrants prospective validation before practice change.
Objective: Observational studies have indicated that immune cells and circulating inflammatory proteins may play a dual role in the progression of COPD; however, the precise mechanisms remain uncertain. The objective of this study was to ascertain the causal relationship between immune cells and COPD and to quantify the potential role of circulating inflammatory proteins as mediators. Methods: A two-sample Mendelian randomisation analysis was conducted involving 731 immune cells, 91 inflammatory proteins and COPD, utilising summary-level data from genome-wide association studies. The causal relationships between immune cells, inflammatory proteins and COPD were sequentially analysed by multivariate Mendelian randomisation and validated using Bayesian weighted Mendelian randomisation. Subsequently, sensitivity analyses were conducted, employing Cochran's Q test to assess heterogeneity, MR-PRESSO and MR-Egger tests to assess pleiotropy, and reverse MR and Steiger directionality tests to rule out reverse causality. Lastly, a two-step approach was employed to ascertain the proportion of inflammatory proteins that mediate immune cell-mediated effects in COPD. Results: The combination of the inverse variance weighting method and the Bayesian weighting algorithm identified 30 immune cells that were found to be causally associated with COPD, as well as eight inflammatory proteins that were associated with COPD. By two-step analysis, six inflammatory proteins were found to mediate the effects of eight immune cell phenotypes on COPD, with CXCL10 having the highest percentage of mediation at 14.49%, followed by IL20RA at 11.47%. Conclusion: This study provides a comprehensive investigation of the causal relationship between immune cells and COPD, as well as an estimation of the proportion of the effect of inflammatory proteins as mediators. These findings facilitate the identification of individuals at high risk of COPD and offer novel insights for early prevention and clinical intervention.
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Wang et al. (2025) conducted an observational in Chronic Obstructive Pulmonary Disease (COPD) (n=394,244). Genetically predicted immune cell phenotypes and circulating inflammatory proteins vs. Unexposed/reference genetic variants was evaluated on Causal association with COPD and mediation proportion of inflammatory proteins. Mendelian randomization identified 30 immune cells and 8 inflammatory proteins causally associated with COPD, with CXCL10 mediating 14.49% of the effect of CD11c on CD62L+ myeloid dendritic cells.
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