Abstract: BACKGROUND: Pulmonary arterial hypertension is a destructive cardiopulmonary disease for which there is no cure. An association between plasma proteins and pulmonary arterial hypertension has been suggested, but the causal relationship has not been specifically elucidated. 
OBJECTIVE: To elucidate the causal relationship between plasma proteome and pulmonary arterial hypertension using a two-sample Mendelian randomization method, thereby searching for potential therapeutic targets for pulmonary arterial hypertension.
METHODS: Plasma Protein Gene-Wide Association Analysis Statistics for 4 907 Aptamer Measurements in 35 559 Icelanders from the Icelandic Database; Genome-wide association analysis statistics for pulmonary arterial hypertension were obtained from the Finn Gen database, version R9, including 234 cases and 265 626 controls. Analyses were performed using Mendelian randomization and Bayesian co-localization analysis, the findings were examined using sensitivity analyses, and protein-protein interaction network maps were constructed to explore the causal relationship between plasma proteins and pulmonary arterial hypertension.
RESULTS AND CONCLUSION: (1) The results of inverse variance weighting, maximum likelihood and Wald ratio methods showed 19 proteins causally associated with pulmonary arterial hypertension (P < 0.05). Among them, 10 plasma proteins, including Beta-1,3-N-acetylglucosaminyltransferase manic fringe (odds ratio [OR]=0.12, 95% confidence interval [CI] 0.02-0.61, P=0.01) and interferon alpha/beta receptor 1 (OR=0.45, 95% CI 0.24-0.84, P=0.012), might be associated with a reduced risk of pulmonary arterial hypertension. In contrast, nine plasma proteins, such as glucoside xylosyltransferase 1 (OR=3.48, 95% CI 1.51-8.00, P=0.003) and plasminogen (OR=42.78, 95% CI 2.49-734.31, P=0.01), might be associated with an increased risk of pulmonary arterial hypertension. After the false discovery rate was corrected, 19 proteins remained significantly associated with pulmonary arterial hypertension. (2) Multiple sensitivity analyses such as the MR-Egger intercept test and leave-one-out method showed no horizontal multiplicity or heterogeneity in the results of the study, indicating the stability of the study’s results. (3) Bayesian co-localization analysis showed that six plasma proteins, including plasminogen (PPH4=1.0) and glucoside xylosyltransferase 1 (PPH4=0.94), had PPH4 > 0.8, suggesting that plasma proteins and the genome-wide association study of pulmonary arterial hypertension had similar causal variance in terms of genetic association. (4) By constructing a protein-protein interaction network map, plasminogen, Annexin A1, fibrinogen gamma chain and matrix metalloproteinase 7 were found to be core proteins. (5) The article used Mendelian randomization analysis to reveal a potential causal association between 4 907 plasma proteins and pulmonary arterial hypertension, suggesting that plasma proteins may be potential therapeutic targets for pulmonary arterial hypertension. The core proteins identified in the study also provide a theoretical basis for further in-depth study of the pathophysiological mechanisms of pulmonary arterial hypertension. Secondly, analyses using the large-scale international databases of Iceland and FinnGen provide new research directions and treatment ideas for pulmonary arterial hypertension in specific populations and environments, as well as ideas and methods that can be used to prevent and treat pulmonary arterial hypertension in China.

Key words: pulmonary arterial hypertension, plasma proteins, protein quantitative trait loci, Mendelian randomization, causality, drug targets, protein interactions