Array-based identification of disease-associated proteins

Abstract: 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.