Poststroke fatigue: hints to a biological mechanism

J Stroke Cerebrovasc Dis. 2015 Mar;24(3):618-21. doi: 10.1016/j.jstrokecerebrovasdis.2014.10.008. Epub 2014 Dec 23.


Background: Poststroke fatigue (PSF) is common, but the biological basis of this fatigue is unknown. We explored the possibility that PSF is related to systemic inflammation by investigating polymorphisms in 2 genes that affect the immune response.

Methods: In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, fatigue was assessed at 30, 90, 180, and 365 days after ischemic stroke using the Fatigue Assessment Scale. Subjects were genotyped for 3 single nucleotide polymorphisms, one in the interleukin-1 receptor antagonist gene (IL1RN; rs4251961, a T/C substitution) and two in the in toll-like receptor-4 (TLR4) gene (1063 A/G [Asp299Gly] rs4986790 and 1363 C/T [Thr399Ile] rs4986791).

Results: Of the 39 participants, 22 (56%) endorsed fatigue during the study. The degree of fatigue was remarkably constant over time and independent of stroke outcome. The C allele of the rs4251961 single nucleotide polymorphism (SNP) in IL1RN was associated with self-reported fatigue (P = .03), whereas the cosegregating polymorphisms in TLR4 were associated with lower levels of fatigue (P= .04).

Conclusions: SNPs in 2 genes with opposing effects on inflammatory immune responses were significantly, but differentially, associated with PSF. These findings suggest a direct link between immune signaling dysregulation and PSF.

Keywords: IL1RN; Poststroke fatigue; TLR4; inflammation; polymorphisms.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Fatigue / diagnosis
  • Fatigue / genetics*
  • Fatigue / immunology
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation / diagnosis
  • Inflammation / genetics*
  • Inflammation / immunology
  • Interleukin 1 Receptor Antagonist Protein / genetics*
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protective Factors
  • Risk Factors
  • Severity of Illness Index
  • Stroke / diagnosis
  • Stroke / genetics*
  • Stroke / immunology
  • Time Factors
  • Toll-Like Receptor 4 / genetics*


  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • TLR4 protein, human
  • Toll-Like Receptor 4