Biomarker and transcriptomics profiles of serum selenium concentrations in patients with heart failure are associated with immunoregulatory processes
Ali A. Al-Mubarak,
George Markousis Mavrogenis,
Xuanxuan Guo,
Marco De Bruyn,
Mintu Nath,
Simon P.R. Romaine,
Niels Grote Beverborg,
Karla Arevalo Gomez,
Sietske N. Zijlstra,
Dirk J. van Veldhuisen,
Nilesh J. Samani,
Adriaan A. Voors,
Peter van der Meer,
Nils Bomer
Affiliations
Ali A. Al-Mubarak
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
George Markousis Mavrogenis
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Xuanxuan Guo
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Marco De Bruyn
Department of Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Mintu Nath
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK; Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
Simon P.R. Romaine
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Niels Grote Beverborg
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Karla Arevalo Gomez
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Sietske N. Zijlstra
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Dirk J. van Veldhuisen
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Nilesh J. Samani
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Adriaan A. Voors
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Peter van der Meer
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Nils Bomer
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Correspondind author. Dept. Experimental Cardiology, University Medical Center Groningen, UMCG Post-zone AB43, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
Background: Low selenium concentrations are associated with worse outcomes in heart failure (HF). However, the underlying pathophysiologic mechanisms remain incompletely understood. Therefore, we aimed to contrast serum selenium concentrations to blood biomarker and transcriptomic profiles in patients with HF. Methods: Circulating biomarkers, whole blood transcriptomics and serum selenium measurements in a cohort of 2328 patients with HF were utilized. Penalized linear regression and gene expression analysis were used to assess biomarker and transcriptomics profiles, respectively. As a proof-of-principle, potential causal effects of selenium on excreted cytokines concentrations were investigated using human peripheral blood mononuclear cells (PBMCs). Results: Mean selenium levels were 60.6 μg/L in Q1 and 122.0 μg/L in Q4. From 356 biomarkers and 20 clinical features, the penalized linear regression model yielded 44 variables with <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 selenium concentrations included: PCSK9, TNFSF13, FGF21 and PAI. Additionally, 148 RNA transcripts were found differentially expressed between high and low selenium status (Padj.<0.05; log-fold-change<|0.25|). Enrichment analyses of the selected biomarkers and RNA transcripts identified similar enriched processes, including regulation processes of leukocyte differentiation and activation, as well as cytokines production. The mRNA expression of two selenoproteins (MSRB1 and GPX4) were strongly correlated with serum selenium, 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 HF. The beneficial effects of higher serum selenium concentrations are likely because of global immunomodulatory effects on the abundance of cytokines. MSRB1 and GPX4 are potential modulators of and should be pursued in future research.
