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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
KTH.
Visa övriga samt affilieringar
2016 (Engelska)Ingår i: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 37, nr 1, s. 132-140Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers. © 2016 John Wiley & Sons A/S.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2016. Vol. 37, nr 1, s. 132-140
Nyckelord [en]
Affinity proteomics, Biomarker discovery, Drug-induced liver injury, Plasma profiling, Suspension bead arrays
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:kth:diva-194625DOI: 10.1111/liv.13174ISI: 000393769900014Scopus ID: 2-s2.0-84977547750OAI: oai:DiVA.org:kth-194625DiVA, id: diva2:1043820
Anmärkning

Correspondence Address: Schuppe-Koistinen, I.email: ina.schuppe-koistinen@scilifelab.se. QC 20161101

Tillgänglig från: 2016-11-01 Skapad: 2016-10-31 Senast uppdaterad: 2018-08-23Bibliografiskt granskad
Ingår i avhandling
1. Array-based identification of disease-associated proteins
Öppna denna publikation i ny flik eller fönster >>Array-based identification of disease-associated proteins
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

To increase our understanding of the human body in both health and disease, proteins can be studied in samples such as plasma and serum to provide a molecular profile of the physiological status. In the work presented in this thesis, array-based methods were used to study associations of protein and autoantibody profiles with disease. The methods included antibody suspension bead arrays for protein profiling and planar antigen arrays or antigen suspension bead arrays for autoantibody profiling.

In Paper I, we studied protein levels in the context of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We identified three proteins, NEFM, RGS18 and SLC25A20, to be significantly elevated in patients with ALS. We also evaluated the diagnostic potential of these proteins, reaching areas under the curves (AUCs) between 0.78 and 0.86 for each of the three proteins individually.

In Paper II, drug-induced liver injury (DILI) cases and controls were studied in four independent cohorts of longitudinal and cross-sectional design and covering a range of drugs. The protein FABP1 was elevated in DILI cases upon initiation of treatment whereas CDH5 were elevated before treatment. Furthermore, we compared FABP1 with the clinically measured alanine aminotransferase (ALT), and identified some aspects in which FABP1 was superior: tissue distribution – FABP1 was not found in skeletal and heart muscle tissue, injuries in which can cause elevations of ALT; kinetics – FABP1 is smaller and has a lower half-life compared to ALT. Both of these circumstances mean that FABP1 as a biomarker has the potential to more accurately reflect ongoing injury.

In Paper III, asthma of different severities, chronic obstructive pulmonary disease and healthy controls from two independent cohorts were studied. The levels of ten proteins were verified to be significantly elevated in severe asthma compared to both mild-to-moderate asthma and healthy controls in both cohorts. We also clustered asthma patients based on their protein profiles and identified six subgroups that could help to guide the appropriate treatment.

In Paper IV, atopic dermatitis (AD) of different severities and healthy controls were studied. Increased autoantibody reactivity to four antigens, KRTAP17-1, HSPA4, S100A12 and S100Z, were observed in AD patients or in any of the two severity disease subgroups compared to controls.

In summary, the work included in this thesis highlights the applicability of protein array-based methods in various contexts and in studying various research questions. Disease-associated proteins were identified and further studies will determine their utility.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2018. s. 69
Serie
TRITA-CBH-FOU ; 2018:28
Nyckelord
Affinity proteomics, Antibody array, Antigen array, Amyotrophic lateral sclerosis, Asthma, Atopic dermatitis, Biomarker discovery, Drug-induced liver injury, Microarray, Plasma, Protein microarray, Protein profiling, Serum, Suspension bead array
Nationell ämneskategori
Medicinsk bioteknologi
Forskningsämne
Bioteknologi
Identifikatorer
urn:nbn:se:kth:diva-233541 (URN)978-91-7729-902-8 (ISBN)
Disputation
2018-09-14, Air & Fire, SciLifeLab, Tomtebodavägen 23A, Solna, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

QC 20180823

Tillgänglig från: 2018-08-23 Skapad: 2018-08-23 Senast uppdaterad: 2018-08-23Bibliografiskt granskad

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Mikus, MariaDrobin, KimiGry, MarcusUhlén, MattiasSchwenk, Jochen MNilsson, P. Anders
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