title: Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes.
abstract: Using global liquid chromatography-mass spectrometry (LC-MS)-based proteomics analyses, we identified 24 serum proteins that were significantly variant between those with type 1 diabetes (T1D) and healthy controls. Functionally, these proteins represent innate immune responses, the activation cascade of complement, inflammatory responses, and blood coagulation. Targeted verification analyses were performed on 52 surrogate peptides representing these proteins, with serum samples from an antibody standardization program cohort of 100 healthy control and 50 type 1 diabetic subjects. 16 peptides were verified as having very good discriminating power, with areas under the receiver operating characteristic curve ≥ 0.8. Further validation with blinded serum samples from an independent cohort (10 healthy control and 10 type 1 diabetics) demonstrated that peptides from platelet basic protein and C1 inhibitor achieved both 100% sensitivity and 100% specificity for classification of samples. The disease specificity of these proteins was assessed using sera from 50 age-matched type 2 diabetic individuals, and a subset of proteins, C1 inhibitor in particular, were exceptionally good discriminators between these two forms of diabetes. The panel of biomarkers distinguishing those with T1D from healthy controls and those with type 2 diabetes suggests that dysregulated innate immune responses may be associated with the development of this disorder.
authors.affiliation: Biological Sciences Division and the 2 Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA. qibin.zhang@pnnl.gov
authors.forename: Qibin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Fillmore
authors.forename: Athena A
authors.initials: AA
authors.lastname: Schepmoes
authors.forename: Therese R W
authors.initials: TR
authors.lastname: Clauss
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gritsenko
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Mueller
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
mesh_terms: D000595:Amino Acid Sequence; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis*; D016022:Case-Control Studies; D002853:Chromatography, Liquid / Q000379:methods; D003174:Complement C1 Inactivator Proteins / Q000032:analysis; D050718:Complement C1 Inhibitor Protein; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology; D007113:Immunity, Innate; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D040901:Proteomics / Q000379:methods*; D012372:ROC Curve; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human