The suppressor of cytokine signaling 3 (SOCS3) gene may play a key role in the pathogenesis of pulmonary arterial hypertension (PAH) and be a potential prognostic biomarker, according to a new study published in the Journal of Cardiovascular Translational Research. 

It is already known that pathogenic changes in DNA methylation may have a part in the onset and progression of PAH. However, their link with patient-derived hemodynamic parameters is not known.

Here, a team of researchers led by Claudio Napoli MD, PhD, from the Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, in Naples, Italy, used the reduced representation bisulfite sequencing (RRBS) platform to compare circulating CD4+ T cells from patients with PAH and those isolated from healthy controls. 

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This way, the researchers identified 631 differentially methylated CpG sites in  408 genes. They then conducted a promoter-restricted network analysis and identified a PAH subnetwork, which included 5 hub differentially-methylated genes and 5 non-hub differentially-methylated genes. Among these, SOCS3 was the most recurrent among the top 10 significant pathways enriching the PAH subnetwork.

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The hypomethylation of SOCS3 was negatively associated with right atrial pressure and positively associated with cardiac index. Moreover, the SOCS3 gene, along with 3 other hub differentially-methylated genes and 1 non-hub differentially-methylated gene, was upregulated at the mRNA level in the peripheral blood of PAH patients compared to healthy controls. SOCS3, a major regulator of inflammation inhibiting cytokine or hormone signaling pathways, was also upregulated at the protein level in PAH patients compared to healthy controls. 

“This is the first network-oriented study which integrates circulating CD4+ T cell DNA methylation signatures, hemodynamic parameters, and validation experiments in PAH patients at first diagnosis or early follow-up,” the researchers wrote. They added that differentially-methylated genes may be useful as potential prognostic biomarkers in PAH.


Benincasa G, Maron BA, Affinito O, et al. Association between circulating CD4+ T cell methylation signatures of network-oriented SOCS3 gene and hemodynamics in patients suffering pulmonary arterial hypertension. J Cardiovasc Transl Res. Published online August 12, 2022. doi:10.1007/s12265-022-10294-1