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* = Presenting author

P140 Proximity Extension Assay technology identifies novel serum biomarkers for predicting Inflammatory Bowel Disease: IBD Character Consortium

R. Kalla*1, N. Kennedy1, F. Hjelm2, E. Modig2, M. Sundell2, B. Andreassen3, D. Bergemalm4, P. Ricanek5, J. Söderholm6, M. Vatn3, J. Halfvarson4, M. Gullberg2, - IBD Character Consortium7, J. Satsangi1

1University of Edinburgh, Gastrointestinal unit, Edinburgh, United Kingdom, 2Olink , Bioscience, Uppsala, Sweden, 3University of Oslo, Institute of Clinical Medicine, Oslo, Norway, 4Örebro University, Department of Gastroenterology, Örebro, Sweden, 5Akershus University Hospital, Department of Gastroenterology, Lørenskog, Norway, 6Linköping University, Gastroenterology, Linköping, Sweden, 7European IBD Character consortium, FP7, Edinburgh, United Kingdom

Background

Technological advances in protein profiling using proximity extension assays (PEA) have transformed our ability to compare concentrations of multiple proteins across biological samples. [1] [2] This technique utilises the high sensitivity and specificity of polymerase chain reaction (PCR) to detect proteins of interest.As part of the European Commission funded IBD Character initiative to discover biomarkers for clinical use using multi-omic technologies (www.ibdcharacter.eu), we performed high-throughput prospective case-control serum profiling to identify protein biomarkers that can predict Inflammatory Bowel Disease (IBD).

Methods

Utilising Proseek Multiplex arrays (Olink Bioscience, Uppsala, Sweden), serum profiling was performed in patients with a new diagnosis of IBD. Our control group consisted of symptomatic individuals. Phenotypic data was captured including age, sex, diagnosis and IBD medications. Statistical analysis was performed using R. Data were normalised and then batch corrected using ComBAT. Linear models were created for each protein including age and sex as covariates. After quality control, data from 186 proteins was available for analysis.

Results

A total of 245 patient serum samples (n=153 newly diagnosed IBD, n=92 symptomatic controls) from 4 IBD centres from Norway, United Kingdom and Sweden were included in the study from December 2012 to June 2014. 70 had Crohn's disease (CD), 70 ulcerative colitis(UC) and 13 Inflammatory Bowel Disease Unclassified (IBDU). The mean age of the entire cohort was 33 years (range 0-79 years) and 54% were female. Multivariable analysis identified a set of 48 protein markers that were significantly associated with IBD. The 5 most significant protein markers were MMP-12 (Holm-adjusted p=3.3 × 10-13), OSM (p=2.4 × 10-12), CXCL9 (p=1.7 × 10-9), MMP10 (p=1.7 × 10-9) and EGFR (p=1.8 × 10-9). Of these five, all except EGFR were upregulated in IBD. The top 2 markers, MMP-12 and OSM were able to discriminate IBD from controls with an area under the receiver operator characteristics curve of 0.81 and 0.75 respectively. Using linear discriminant analysis, a combined biomarker consisting of MMP-12 and OSM was able to discriminate IBD from controls with a sensitivity and specificity of 80% and 72% respectively.

Conclusion

We have identified PEA-based serum biomarkers that can predict IBD. These data demonstrate the translational potential of a PEA based technology in IBD diagnostics and its ability to identify novel proteins that may be relevant in disease pathogenesis.

References:

[1] Assarsson E, Lundberg M, Holmqvist G, Björkesten J, Thorsen SB, Ekman D, Eriksson A, Rennel Dickens E, Ohlsson S, Edfeldt G, Andersson A-C, Lindstedt P, Stenvang J, Gullberg M, Fredriksson S, (2014), Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability, PLOS one, doi: 10.1371/journal.pone.0095192. eCollection 2014, 2014-04-22

[2] Thorsen SB, Lundberg M, Villablanca A, Christensen SLT, Christensen Belling K, Sander Nielsen B, Knowles M, Gee N, Nielsen HJ, Brünner N, Christensen IJ, Fredriksson S, Stenvang J, and Assarsson E, (2013), Detection of serological biomarkers by proximity extension assay for detection of colorectal neoplasias in symptomatic individuals, J Transl Med, doi: 10.1186/1479-5876-11-253, 2013-10-01