Circulating CD4+T/methylation signatures of network-oriented SOCS3, ITGAL, NFIC, NCOR2, PGK1 genes associate with hemodynamics in pulmonary arterial hypertension patients

Abstract Background CD4+ T cells are associated with pulmonary arterial hypertension (PAH) pathogenesis but mechanistic insights limited. Purpose To identify differential methylation signatures in healthy controls vs PAH and evaluate a putative association the cardiopulmonary hemodynamic profile of affected patients. Methods We used RRBS platform to DNA methylome CLEOPAHTRA clinical trial. Results Differentially methylated CpG sites (N=631) annotated N=408 genes (DMGs). Most them (65%) were hypermethylated localized distal intergenic (36%) promoter regions (31%). Promoter-related network analysis established subnetwork highlighting 5 hub DMGs (SOCS3, GNAS, ITGAL, NCOR2, NFIC) non-hub (NR4A2, GRM2, PGK1, STMN1, LIMS2) as potential candidate (Figure 1). The Infinium Human MethylationEPIC BeadChip on from an independent study population confirmed global RRBS-methylation trends. Both idiopathic Associated-PAH, each these 10 network-oriented was strongly correlated at least one parameter such right atrial pressure (RAP), cardiac index (CI), mean (mPAP), vascular resistance (PVR), capillary wedge (PCWP) 2). In addition, mRNA levels NFIC, PGK1 IL-6-STAT3-SOCS3 signaling axis significantly upregulated PBMCs patients suggesting drug targets. Furthermore, both SOCS3 positively (CI) whereas RAP inversely CI Associated non-invasive biomarkers. Conclusions This hypothesis-generating shows for first time that circulating signatures, inclusive SOCS3, may yield insight into pro-inflammatory mechanisms exacerbate remodeling suggest biomarkers optimize patient phenotyping and, possibly, prognostication PAH. FUNDunding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): PRIN2017F8ZB89 Italian Ministry University Research (MIUR) (PI Prof Napoli) Ricerca Corrente (RC) 2019 Health Prof. Napoli). Figure 1 2