Abstract
Ankylosing Spondylitis (AS) is a common inflammatory rheumatic disease with a predilection for the axial skeleton, affecting 0.2% of the population. Current diagnostic criteria rely on a composite of clinical and radiological changes, with a mean time to diagnosis of 5 to 10 years. In this study we employed nano liquid-chromatography mass spectrometry analysis to detect and quantify proteins and small compounds including endogenous peptides and metabolites in serum from 18 AS patients and nine healthy individuals. We identified a total of 316 proteins in serum, of which 22 showed significant up- or down-regulation (p < 0.05) in AS patients. Receiver operating characteristic analysis of combined levels of serum amyloid P component and inter-α-trypsin inhibitor heavy chain 1 revealed high diagnostic value for Ankylosing Spondylitis (area under the curve = 0.98). We also depleted individual sera of proteins to analyze endogenous peptides and metabolic compounds. We detected more than 7000 molecular features in patients and healthy individuals. Quantitative MS analysis revealed compound profiles that correlate with the clinical assessment of disease activity. One molecular feature identified as a Vitamin D3 metabolite—(23S,25R)-25-hydroxyvitamin D3 26,23-peroxylactone—was down-regulated in AS. The ratio of this vitamin D metabolite versus vitamin D binding protein serum levels was also altered in AS as compared with controls. These changes may contribute to pathological skeletal changes in AS. Our study is the first example of an integration of proteomic and metabolomic techniques to find new biomarker candidates for the diagnosis of Ankylosing Spondylitis.
Highlights
From the ‡Henry Wellcome Building for Cellular and Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK, §Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, Oxford, OX3 9DS, UK, ¶University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, appropriate ethical permission Queensland (AU)
Since the early diagnosis of AS can have an impact on the treatment of subjects with AS, we present a set of molecular features that can be used to differentiate the AS patients according to the severity of symptoms, represented by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
Applying Linear Models for Microarray (LIMMA) data [31] we identified 22 proteins which were significantly up- or down- regulated in AS patients compared with healthy individuals (Table II)
Summary
39 Control a Used in metabolomic study only. such as C-reactive protein, IgG, or IgA have not archived sufficient diagnostic sensitivity or specificity [14, 15]. 39 Control a Used in metabolomic study only Such as C-reactive protein, IgG, or IgA have not archived sufficient diagnostic sensitivity or specificity [14, 15]. In the present discovery study, we show that the mass profile of proteins and small compounds in the serum of individuals can be used to differentiate between AS subjects and healthy individuals. 25hydroxyl Vitamin D and its metabolites are involved in the regulation of bone formation [25], providing a potential link to AS-associated osteoporosis.
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