Abstract
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.