Lin Jie, Zhang Zhan, Zhou Qiang, Shi Jiayi, Li Wanqing, Lin Sen, Tang Hu, Zhang Zheyu, Chen Tianfeng, Cai Xiaojun, Cao Longhe
Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People's Hospital), Wenzhou, China.
Department of Otolaryngology, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People's Hospital), Wenzhou, China.
Environ Toxicol. 2025 Mar 11. doi: 10.1002/tox.24506.
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, FDR = 2.21 × 10), CD8 on CD28- CD8br (95% CI: 1.0007-1.0020, p = 4.01 × 10，FDR = 5.70 × 10), CD62L on monocyte (95% CI: 0.9985-0.9995，p = 1.06 × 10，FDR = 9.20 × 10), CD8br% leukocyte (95% CI: 1.0006-1.0019，p = 1.07 × 10，FDR = 1.14 × 10). 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.
越来越多的证据表明，各种免疫细胞表型与哮喘的发生发展之间存在关联。然而，特定免疫细胞表型是否可能因果性地导致哮喘风险，目前仍不完全清楚。尽管需要进一步研究来验证这一说法，但我们的研究更深入地探讨了这种关系，并为新的治疗方法铺平了道路。我们最初的目标是揭示731种免疫细胞表型与哮喘之间的因果关系；进行了双向孟德尔随机化（MR）分析。我们利用先前发表的全基因组关联研究（GWAS）总结，研究了哮喘中的731种免疫细胞表型。通过进行MR分析，我们解读了它们之间潜在的因果关系。我们的分析方法包括逆方差加权平均值、加权中位数（WM）建模和基于模式的方法。为确保研究结果的稳健性和准确性，我们采用MR-PRESSO、 Cochr an检验、留一法和MR-Egger方法进行了敏感性分析。此外，我们进行了反向MR分析，以检验潜在的反向因果关系。我们的研究揭示了43种与哮喘风险存在因果联系的免疫表型。经过Bonferroni校正和敏感性分析，我们确定了四种具有强因果关联和可靠性的免疫表型，它们分别是：树突状细胞上的HLA DR（95%置信区间：1.0008 - 1.0014，p = 4.26×10，FDR = 2.21×10）、CD28 - CD8br上的CD8（95%置信区间：1.0007 - 1.0020，p = 4.01×10，FDR = 5.70×10）、单核细胞上的CD62L（95%置信区间：0.9985 - 0.9995，p = 1.06×10，FDR = 9.20×10）、白细胞上的CD8br%（95%置信区间：1.0006 - 1.0019，p = 1.07×10，FDR = 1.14×10）。我们证实了所有这些免疫表型的高度共同遗传性，这表明它们对哮喘的发展有影响。此外，反向MR证实哮喘与免疫细胞表型之间不存在因果关联。我们的研究提供了不同免疫表型的证据，这些表型对哮喘要么有益要么有害。鉴于哮喘是一种广泛的疾病且包含复杂的免疫机制，这项研究可能会带来更好的治疗效果和长期的哮喘治疗策略。
