Proteomic and transcriptomics profiles of serum selenium concentrations in patients with heart failure are associated with immunoregulatory processes
Authors: Bomer N , Al-Mubarak A A , Markousis Mavrogenis G , Guo X , De Bruyn M , Nath M , Romaine S P R , Grote Beverborg N , Arevalo Gomez K , Zijlstra S N , Van Veldhuisen D J , Samani N J , Voors A A , Van Der Meer P 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Research Council, through the Open Competition ENW-KLEIN grant

Background
Low selenium concentrations are associated with worse outcomes in patients with heart failure (HF). However, the underlying pathophysiologic mechanisms remain incompletely understood. Therefore, we aimed to contrast serum selenium concentrations to blood proteomic and transcriptomic profiles in patients with HF.

Methods
Circulating proteins, whole blood transcriptomics and serum selenium measurements in a cohort of 2328 patients with worsening HF (BIOSTAT-CHF) were utilized to assess underlying pathophysiology. Penalized linear regression and gene expression analysis were used to assess proteins and transcriptomics profiles based on selenium concentrations, respectively. String database v11.5 was used for enrichment analyses. Additionally analyses of the association between genes encoding selenoproteins in relation to serum selenium and all-cause mortality were performed. Potential causality was investigated by supplementing human peripheral blood mononuclear cells (PBMCs) with selenium and measuring the concentrations of 18 different cytokines.

Results
From 356 biomarkers and 20 clinical features, the penalized linear regression model yielded 44 variables with &lt;5% marginal false discovery rate as predictors of serum selenium. Biomarkers associated positively with selenium concentrations included: epidermal growth factor receptor (EGFR), IFN-gamma-R1, CD4, GDF15, and IL10. Biomarkers associated negatively with low selenium concentrations included: PCSK9, SPON2, TNFSF13, FGF21 and PAI. In addition, 148 RNA transcripts were found differentially expressed between high and low Se status (Padj.&lt;0.05; fold change&lt;|0.25|). Enrichment analyses of the selected biomarkers and the selected RNA transcripts identified similar enriched processes, including regulation processes of leukocyte differentiation and activation, as well as cytokines production. The expression of two gene encoding selenoproteins (MSRB1 and GPX4) were strongly correlated with serum selenium after multiple corrections, while GPX4, SELENOK, and SELENOS were associated with prognosis. In the in-vitro setting, PBMCs supplemented with selenium showed significantly lower abundance of several (pro-)inflammatory cytokines.

Conclusion
These data suggest that immunoregulation is an important mechanism through which selenium might have beneficial roles in heart failure. The beneficial effects of higher serum selenium concentrations are likely because of global immunomodulatory effects on the abundance of cytokines. MSRB1 and GPX4 are interesting targets as potential modulators of this immunoregulatory effect of selenium and should be pursued in future research.Cytokines concentrations