title: Blood Proteomic Profiling in Inherited (ATTRm) and Acquired (ATTRwt) Forms of Transthyretin-Associated Cardiac Amyloidosis.
abstract: Transthyretin-associated forms of cardiac amyloidosis are fatal protein misfolding diseases that can be inherited (ATTRm) or acquired (ATTRwt). An accurate diagnosis of ATTR amyloidosis can be challenging as biopsy evidence, usually from the affected organ, is required. Precise biomarkers for ATTR disease identification and monitoring are undiscovered, disease-specific therapeutic options are needed, and the current understanding of ATTR molecular pathogenesis is limited. The aim of this study was to investigate and compare the serum proteomes in ATTRm and ATTRwt cardiac amyloidosis to identify differentially expressed blood proteins that were disease-specific. Using multiple-reaction monitoring mass spectrometry (MRM-MS), the concentrations of 160 proteins were analyzed in serum samples from ATTRm and ATTRwt patients, and a healthy control group. Patient and control sera were matched to age (≥60 years), gender (male), and race (Caucasian). The circulating concentrations of 123/160 proteins were significantly different in patient vs control sera; TTR and retinol-binding protein (RBP4) levels were significantly decreased (p < 0.03) in ATTRm compared to controls. In ATTRm, 14/123 proteins were identified as unique to that group and found generally to be lower than controls; moreover, the concentrations of RBP4 and 6 other proteins in this group were significantly different (p < 0.04) compared to ATTRwt. Predicted interactions among the 14 proteins unique to ATTRm were categorized as reaction and binding associations. Alternatively, 27 proteins were found to be unique to ATTRwt with associated interactions defined as activation, catalysis, and inhibition, in addition to reaction and binding. This study demonstrates significant proteomic differences between ATTR patient and control sera, and disease-associated variations in circulating levels of several proteins including TTR and RBP4. The identification of serum proteins unique to ATTRm and ATTRwt cardiac amyloidosis may have diagnostic and prognostic utility, and may provide important clues about disease mechanisms.
authors.affiliation: Amyloidosis Center and ‡Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
authors.forename: Gloria G
authors.identifier: 0000-0003-4541-9713
authors.initials: GG
authors.lastname: Chan
authors.affiliation: Amyloidosis Center and ‡Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Koch
authors.affiliation: Amyloidosis Center and ‡Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connors
mesh_terms: D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000097:blood* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000097:blood*; D001706:Biopsy; D001798:Blood Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020543:Proteome / Q000235:genetics; D057165:Proteostasis Deficiencies / Q000097:blood* / Q000235:genetics / Q000473:pathology
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D020543:Proteome
keywords: DAVID; MRM-MS; PANTHER; STRING; UniprotKB; amyloidosis; biomarker; cardiomyopathy; familial ATTR; serum; wild-type ATTR