Lian Huilin, Chen Ruifang, Zeng Youjie, Guo Ren, Li Dai
Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China.
Medical Experimental Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Medicine (Baltimore). 2025 Mar 7;104(10):e41737. doi: 10.1097/MD.0000000000041737.
The causal association between pulmonary arterial hypertension (PAH) and autoimmune diseases remains uncertain. This study aimed to assess the causal associations between PAH and autoimmune diseases using bidirectional Mendelian randomization (MR) analyses. Genome-wide association summary statistics for PAH, asthma, myasthenia gravis, rheumatoid arthritis (RA), systemic lupus erythematosus, and type 1 diabetes mellitus were obtained from publicly accessible databases. The primary MR approach used was the inverse variance weighted method. Sensitivity analyses were conducted to test the robustness of the MR findings, including tests for heterogeneity, horizontal pleiotropy, and leave-one-out analysis, ensuring the reliability and validity of the results. Ultimately, transcriptome analysis was used for GO, KEGG enrichment analysis and protein interaction network. Bidirectional Mendelian randomization analysis found a causal relationship between PAH and RA (OR [95% CI] > 1; P < .05). Enrichment analysis further revealed the common molecular mechanisms of these 2 diseases, especially the dysfunction of chemokine pathway and other inflammation-related signaling pathways. Additionally, the study uncovered the core genes within the co-morbidity-associated protein-protein interaction network, including CCL5, CCL9, and VCAM1. Transcription factor (TF) network analysis showed that TFs such as GATA1, JUN and RELA were significantly up-regulated in PAH, and they play a key role in regulating cell proliferation and immune response. The study found a bidirectional positive causal link between PAH and RA. Dysregulation of the chemokine pathway and other inflammation-related signaling pathways may be momentous factors driving the progression of PAH and RA.
肺动脉高压（PAH）与自身免疫性疾病之间的因果关联仍不明确。本研究旨在通过双向孟德尔随机化（MR）分析评估PAH与自身免疫性疾病之间的因果关联。从公开可用的数据库中获取了PAH、哮喘、重症肌无力、类风湿关节炎（RA）、系统性红斑狼疮和1型糖尿病的全基因组关联汇总统计数据。使用的主要MR方法是逆方差加权法。进行了敏感性分析以检验MR结果的稳健性，包括异质性检验、水平多效性检验和留一法分析，以确保结果的可靠性和有效性。最终，转录组分析用于基因本体（GO）、京都基因与基因组百科全书（KEGG）富集分析和蛋白质相互作用网络分析。双向孟德尔随机化分析发现PAH与RA之间存在因果关系（比值比[95%置信区间]>1；P<.05）。富集分析进一步揭示了这两种疾病的共同分子机制，尤其是趋化因子途径和其他炎症相关信号通路的功能障碍。此外，该研究还揭示了共病相关蛋白质-蛋白质相互作用网络中的核心基因，包括CCL5、CCL9和血管细胞黏附分子1（VCAM1）。转录因子（TF）网络分析表明，GATA1、JUN和RELA等TF在PAH中显著上调，它们在调节细胞增殖和免疫反应中起关键作用。该研究发现PAH与RA之间存在双向正因果联系。趋化因子途径和其他炎症相关信号通路的失调可能是推动PAH和RA进展的重要因素。
