title: Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model.
abstract: BACKGROUND
  Determinations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model.
  
  
  METHODS
  A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure.
  
  
  RESULTS
  Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels.
  
  
  CONCLUSIONS
  Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Pietzner
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Engelmann
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Golchert
authors.affiliation: Medical Clinic I, University of Lübeck, Experimental and Clinical Endocrinology, Ratzeburger Allee 160, Zentralklinikum (Haus 40), 23538, Lübeck, Germany.
authors.forename: Anna-Luise
authors.initials: AL
authors.lastname: Dirk
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Hammer
authors.affiliation: Medical Clinic I, University of Lübeck, Experimental and Clinical Endocrinology, Ratzeburger Allee 160, Zentralklinikum (Haus 40), 23538, Lübeck, Germany.
authors.forename: K Alexander
authors.initials: KA
authors.lastname: Iwen
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.|Private Practice Endocrinology, Krämpferstraße 6, 99094, Erfurt, Germany.
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.affiliation: Department of Endocrinology and Metabolism, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Führer
authors.affiliation: Department of Neurology, University of Lübeck, Ratzeburger Allee 169, 23538, Lübeck, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Münte
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Research Centre for Prevention and Health, Glostrup University Hospital, Nordre Ringvej 57, 2600, Glostrup, Denmark.
authors.forename: Nele
authors.initials: N
authors.lastname: Friedrich
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany.|ZIK-FunGene (Zentrum für Innovationskompetenz - Funktionelle Genomforschung), Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 15a, D-17475, Greifswald, Germany. georg.homuth@uni-greifswald.de.|ZIK-FunGene (Zentrum für Innovationskompetenz - Funktionelle Genomforschung), Greifswald, Germany. georg.homuth@uni-greifswald.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Medical Clinic I, University of Lübeck, Experimental and Clinical Endocrinology, Ratzeburger Allee 160, Zentralklinikum (Haus 40), 23538, Lübeck, Germany. georg.brabant@uksh.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Brabant
mesh_terms: D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008297:Male; D055442:Metabolome; D010949:Plasma / Q000737:chemistry / Q000378:metabolism*; D020543:Proteome; D015203:Reproducibility of Results; D013963:Thyroid Hormones / Q000097:blood; D013971:Thyrotoxicosis / Q000097:blood* / Q000139:chemically induced; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D020543:Proteome; D013963:Thyroid Hormones; D013972:Thyrotropin; D013974:Thyroxine
keywords: Hyperthyroidism; Metabolomics; Proteomics; Thyroid function; Thyrotoxicosis