Chronic inflammation markers and cytokine-specific autoantibodies in Danish blood donors with restless legs syndrome

Joseph Dowsett,Erik Sørensen,Christian Erikstrup,Ole Birger Pedersen,Maria Didriksen,Jesper Eugen-Olsen,Margit Hørup Larsen,Lise Wegner Thørner,Jakob Hjorth Von Stemann,Karina Banasik,Morten Bagge Hansen,Sisse Rye Ostrowski

doi:10.1038/s41598-022-05658-1

Abstract

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers’ quality of sleep and health-related quality of life. The pathophysiology of RLS is poorly understood and research focusing on the link between RLS and inflammation has been limited. Our study aimed to investigate whether chronic inflammation markers C-reactive protein (CRP) and soluble urokinase-type plasminogen activator receptor (suPAR), as well plasma levels of five different cytokine-specific autoantibodies (c-aAb), i.e. modulators of inflammation, associate with RLS in otherwise healthy individuals. CRP, suPAR and c-aAb were measured in plasma samples of participants from the Danish Blood Donor Study in 2010. Returning donors between 2015 and 2018 completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment, resulting in datasets with RLS assessment and values for CRP (N = 3564), suPAR (N = 2546) and c-aAb (N = 1478). We performed logistic regression models using the CRP, suPAR or c-aAb as the independent variable and RLS status as the dependent variable, adjusted for appropriate covariates. Our study indicates that a high concentration of CRP is associated with RLS, while an increased probability of experiencing frequent RLS symptoms in those with an elevated plasma suPAR level appears to be mediated through lifestyle factors. We additionally report that a high titer of autoantibodies specific against the cytokine interferon-alpha was associated with RLS. Our results support the existence of links between systemic inflammation and RLS, though further RLS studies on CRP, suPAR and c-aAb in larger cohorts are warranted to confirm our findings and further reveal the hitherto underexplored links between RLS and inflammation.

Highlights

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers’ quality of sleep and health-related quality of life
For the soluble urokinasetype plasminogen activator receptor (suPAR) analysis, plasma suPAR levels, RLS status and covariate data were available in N = 2546 Danish Blood Donor Study (DBDS) participants, of which 126 (4.9%) were diagnosed as RLS cases, including 12 who experienced frequent RLS symptoms
We examined whether historical plasma measurements of the chronic inflammation markers hsCRP and suPAR, as well as five cytokine-specific autoantibodies (c-aAb), were associated with RLS in otherwise healthy Danish blood donors

Summary

Introduction

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers’ quality of sleep and health-related quality of life. Our study aimed to investigate whether chronic inflammation markers C-reactive protein (CRP) and soluble urokinasetype plasminogen activator receptor (suPAR), as well plasma levels of five different cytokine-specific autoantibodies (c-aAb), i.e. modulators of inflammation, associate with RLS in otherwise healthy individuals. Our study indicates that a high concentration of CRP is associated with RLS, while an increased probability of experiencing frequent RLS symptoms in those with an elevated plasma suPAR level appears to be mediated through lifestyle factors. Research focusing on the link between RLS and inflammation has been limited to only a few small studies, with discrepant findings Some of these studies, for example, report an association between RLS and circulating levels of the inflammatory markers C-reactive protein (CRP)[10,11], interleukin-6 (IL-6)[12] and neutrophil-to-lymphocyte ratio (NLR)[13], while others do not find associations with C RP12,14, IL-614 and N LR15,16. Their exact role, if any, is not well known, as they may both contribute to the regulation of cytokine homeostasis and play pathogenic roles in several diseases[23]

Methods

Results

Conclusion