Iron inflammation, and early death in adults with sickle cell disease
Beers, E.J. van, Yang, Y., Raghavachari, N., Allen, D., Nichols, J., Mendelsohn, L., Nekhai, S., Gordeu, V.R., Taylor Vi, J.G., Kato, G.J.
Voorzitter(s): mw. prof.dr. J. de Graaf, Nijmegen & mw. dr. E.J.M. Mattijssen, Arnhem
Locatie(s): Auditorium 2
Categorie(ën):
Introduction: Patients with sickle cell disease are marked by a state of chronic inflammation but the cause of this inflammation and the relevance to patient survival are unknown.
Aim od the study: To assess the relationship between iron, inflammation and early death in sickle cell disease.
Materials and Methods: Registry study of sickle cell disease patients that were followed from February 1, 2001, through January 2011 at the NIH Campus, Bethesda, with a nested case control genetics substudy, supplemented with a hypothesis generating gene expression study. (ClinicalTrials.gov identifier NCT00011648 and NCT00072826)
Results: Using peripheral blood mononuclear cell transcriptome profile hierarchical clustering we classified 24 patients and 11 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll like receptor system (TLR4, TLR7 and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed the microarray based classification and showed that PBMC ferritin light chain, TLR4 and interleukin-6 expression was more than 100-fold higher in patients than in controls (P<0.001) and highly correlated to each other (P<0.001). In a cohort of sickle cell disease patients (n=161), plasma levels of interleukin-6 were most strongly correlated with the inflammatory C-reactive protein (rho=0.496, p<0.001). In a Mendelian randomization experiment 14 sickle cell disease patients with a ferroportin variant that causes intracellular iron accumulation, had significantly higher levels of interleukin-6 and C-reactive protein compared to 14 patients with the wildtype allele, implying a causal effect.(P<0.05) Finally, in a cohort of 412 patients with sickle cell disease followed for a median period of 47 months, (IQR 24-82, range 2-132), C-reactive protein was strongly and independently associated with early death (hazard ratio 3.0, 95% CI 1.7-5.2, P<0.001).
Conclusion and relevance: Gene expression markers of high intracellular iron in patients with SCD are associated with markers of steady state inflammation and mortality. The results support a hypothetical model in which intracellular iron promotes clinically significant inflammatory pathways such as TLR system and the inflammasome, identifying important new pathways for therapeutic intervention.
- Over Beers, E.J. van
- Over Yang, Y.
- Over Raghavachari, N.
- Over Allen, D.
- Over Nichols, J.
- Over Mendelsohn, L.
- Over Nekhai, S.
- Over Gordeu, V.R.
- Over Taylor Vi, J.G.
- Over Kato, G.J.