OMICS and iron metabolism in ME

Genomics in ME

Gene variants of TF, TFRC, and HPX have been identified as risk loci in ME patients (1):




Slide from: Whole Genome Sequencing and Analysis of ME/CFS
https://www.youtube.com/watch?v=nIJX-Q7w_Z4


Serotransferrin (usually just called transferrin), TF: iron-binding protein

Transferrin receptor, TFRC: plasma membrane protein that allows cellular uptake of iron-loaded transferrin

Hemopexin, HPX: a protein that binds free heme (or met-heme) and transport it to the liver for break-down and iron recovery.

Haptoglobin, HP: a protein that binds free hemoglobin and transport it to the liver for break-down and iron recovery.

Hemopexin and haptoglobin prevent heme toxicity.

Proteomics in ME

Serotransferrin precursor (gene: TF), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 105

2) ME patients: 141

3) Post treatment Lyme patients: 105

Transferrin variant fragment  (gene: TF), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 104

2) ME patients: 130

3) Post treatment Lyme patients: 99

Transferrin receptor protein 1 (gene: TFRC), number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2):

1) Controls: 1

2) ME patients: 2

3) Post treatment Lyme patients: 3

Haptoglobin precursor (gene: HP) , number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2).

1) Controls: 30

2) ME patients: 39

3) Post treatment Lyme patients: 34

Hemopexin precursor (gene: HPX) , number of unique peptides identified in the cerebrospinal fluid (table S1 in ref 2).

1) Controls: 61

2) ME patients: 197

3) Post treatment Lyme patients: 189

Another proteome study on cerebrospinal fluid from ME patients also showed increased levels of hemopexin and haptoglobin (3).

Metabolomics in ME

A metabolomic study on plasma from ME patients showed increased levels of heme (4).

Methemoglobin in ME

A study showed increased levels of methemoglobin in ME patients. Methemoglobin was found to be the major component associated with variation in symptom expression in ME patients (R(2) = 0.99, P <0.00001), which included fatigue, musculoskeletal symptoms, pain and sleep disturbance (5).

Activated macrophages produce an inducible NO synthase (iNOS or NOS2). This NO produced during inflammation and other oxygen reactive species results in conversion of hemoglobin to methemoglobin, and this consequently results in an increased rigidity of the red blood cell (RBC) with increased RBC lysis (6).  

Methemoglobin is an activator of endothelial cells by stimulation of IL-6, IL-8 and E-selectin (6).

Red blood cell deformability is diminished in ME patients (7).

Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME (8).

References:

1) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

2) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

3) Baraniuk et al: A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid. BMC Neurol. 2005 Dec 1;5:22. https://www.ncbi.nlm.nih.gov/pubmed/16321154

4) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

5) Richards et al: Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep. 2000;5(1):35-41. https://www.ncbi.nlm.nih.gov/pubmed/10905542

6) Umbreit: Methemoglobin--it's not just blue: a concise review. Am J Hematol. 2007 Feb;82(2):134-44. https://www.ncbi.nlm.nih.gov/pubmed/16986127

7) Saha et al: Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome. Clin Hemorheol Microcirc. 2019;71(1):113-116. doi: 10.3233/CH-180469. https://www.ncbi.nlm.nih.gov/pubmed/30594919

8) Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME. https://followmeindenmark.blogspot.com/2019/09/genomics-proteomics-and-transcriptomics.html