Bioinformatic analysis of proteomic data for iron, inflammation, and hypoxic pathways in restless legs syndrome

Shin, Jai Moo; Lee, Jung Hun; Kim, Hyeyoon; Lee, Da Hye; Baek, Kwang Hyun; Sunwoo, Jun Sang; Byun, Jung Ick; Kim, Tae Joon; Jun, Ji Hae; Han, Dohyun; Jung, Ki Young

doi:10.1016/j.sleep.2020.09.002

Cited by 20 publications

(20 citation statements)

References 34 publications

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“…Hypoxic-inducible factors are essential regulators of inflammation 58 and have previously been associated with RLS 55 . A small proteomic analysis study also reported that eight proteins out of 492 tested were differentially expressed in RLS patients, of which all eight proteins were related to inflammation 59 . Their enrichment pathway and network analysis revealed indirect connections to proteins related to hypoxic pathways.…”

Section: Discussionmentioning

confidence: 93%

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

Dowsett

Didriksen

Stemann

et al. 2022

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 93%

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

Dowsett

Didriksen

Stemann

et al. 2022

Sci Rep

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“… 40 To date, there is no reported association between APOC-II and RLS; nevertheless, a higher prevalence of hypercholesterolemia has been previously noted in these patients, 41 , 42 even if the mechanisms might be complex and influenced by comorbidities. 43 In a study by Patton et al, proteomic analysis of CSF samples from 5 patients with RLS identified a differential downregulation of another apolipoprotein, APOA-I, 32 while a recent work investigating serum proteome of 6 patients 35 reported substantial upregulation of APOH, which is involved in blood coagulation. An association between vascular risk factors of cardiac disease and RLS has previously been established.…”

Section: Discussionmentioning

confidence: 99%

“… 32 Likewise, upregulation of DBP was reported in the serum of a very small sample of RLS patients. 35 Along with its role in regulating vitamin D metabolites, DBP scavenges toxins released during cell injury 52 and modulates the immune response. 53 In addition, variations of its level of expression in the CSF has been associated with multiple neurodegenerative disorders, including Parkinson’s disease and multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Searching for Novel Candidate Biomarkers of RLS in Blood by Proteomic Analysis

Mondello

Kobeissy

Mechref

et al. 2021

NSS

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Purpose We performed comparative proteomic analyses of blood of patients with RLS and healthy individuals aiming to identify potential biomarker and therapeutic target candidate for RLS. Patients and Methods Blood serum samples from 12 patients with a clinical diagnosis of RLS (8 females and 4 males, with a mean age of 68.52 years) and 10 healthy controls (5 females and 5 males, with a mean age of 67.61 years) underwent proteomic profiling by liquid chromatography coupled with tandem mass spectrometry. Pathway analysis incorporating protein–protein interaction networks was carried out to identify pathological processes linked to the differentially expressed proteins. Results We quantified 272 proteins in patients with RLS and healthy controls, of which 243 were shared. Five proteins – apolipoprotein C-II, leucine-rich alpha-2-glycoprotein 1, FLJ92374, extracellular matrix protein 1, and FLJ93143 – were substantially increased in RLS patients, whereas nine proteins – vitamin D-binding protein, FLJ78071, alpha-1-antitrypsin, CD5 antigen-like, haptoglobin, fibrinogen alpha chain, complement factor H-related protein 1, platelet factor 4, and plasma protease C1 inhibitor – were decreased. Bioinformatics analyses revealed that these proteins were linked to 1) inflammatory and immune response, and complement activation, 2) brain-related development, cell aging, and memory disorders, 3) pregnancy and associated complications, 4) myocardial infarction, and 5) reactive oxygen species generation and subsequent diabetes mellitus. Conclusion Our findings shed light on the multifactorial nature of RLS and identified a set of circulating proteins that may have clinical importance as biomarkers and therapeutic targets.

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“…(18,19) RLS has been associated with inflammation, immune disorders, iron deficiency, peripheral neuropathy, hypoxia, endorphin deficiency, autonomic dysfunction, post-infectious states, and most recently, MCAS. (20)(21)(22)(23)(24)(25) In a review of secondary RLS, it was found that inflammation and/or immune disturbances were present in 95% of the 38 highly associated disorders, diseases, and conditions. (20) A single case report detailed a man who had short-lived RLS that occurred during acute COVID-19 infection.…”

Section: Introductionmentioning

confidence: 99%

Restless legs syndrome is associated with long-COVID in women

Weinstock

Brook²,

Walters

et al. 2022

Journal of Clinical Sleep Medicine

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Journal of Clinical Sleep Medicine is dedicated to advancing the science of clinical sleep medicine. In order to provide subscribers with access to new scientific developments as early as possible, accepted papers are posted prior to their final publication in an issue.These papers are posted as received-without copyediting or formatting by the publisher. In some instances, substantial changes are made during the copyediting and formatting processes; therefore, the final version of the paper may differ significantly from this version.

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Bioinformatic analysis of proteomic data for iron, inflammation, and hypoxic pathways in restless legs syndrome

Cited by 20 publications

References 34 publications

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

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

Searching for Novel Candidate Biomarkers of RLS in Blood by Proteomic Analysis

Restless legs syndrome is associated with long-COVID in women

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