Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke
Stroke is a common disorder with significant morbidity and mortality, and complex aetiology involving both environmental and genetic risk factors. Although some of the major risk factors for stoke, such as smoking and hypertension, are well-documented, the underlying genetic and detailed molecular mechanisms remain elusive. Exploring the relevant biochemical pathways may contribute to the clinical diagnosis of stroke and shed light on its aetiology. A comparative proteomic analysis of blood serum of a pair of monozygotic (MZ) twins discordant for ischaemic stroke (IS) was performed using a label-free quantitative proteomics approach. To overcome the limit of reproducibility in the serum preparation, two separate runs were performed, each consisting of three technical replicates per sample. Biological processes associated with proteins differentially expressed between the twins were explored with gene ontology (GO) classification using the functional analysis tool g:Profiler. ANOVA test performed in Progenesis LC-MS identified 179 (run 1) and 209 (run 2) proteins as differentially expressed between the affected and unaffected twin (p < 0.05). Furthermore, the level of serum fibulin 1, an extracellular matrix protein associated with arterial stiffness, was on average 13.37-fold higher in the affected twin. Each dataset was then analysed independently, and the proteins were classified according to GO terms. The categories overrepresented in the affected twin predominantly corresponded to stroke-relevant processes, including wound healing, blood coagulation and haemostasis, with a high proportion of the proteins overexpressed in the affected twin associated with these terms. By contrast, in the unaffected twin diagnosed with atopic dermatitis, there were increased levels of keratin proteins and GO terms associated with skin development. The identification of cellular pathways enriched in IS as well as the upregulation of fibulin 1 sheds new light on the underlying disease-causing mechanisms at the molecular level. Our findings of distinct proteomic signatures associated with IS and atopic dermatitis suggest proteomic profiling could be used as a general approach for improved diagnostic, prognostic and therapeutic strategies.
KeywordsProteomics Stroke Biomarker Monozygotic twins Fibulin 1 Gene
We would like to thank the FingerPrints Proteomics Facility, School of Life Sciences, University of Dundee for the proteomic and mass spectrometry analysis, and The Leverhulme Trade Charities Trust for a bursary to NV.
RCL: Parkinson’s UK Grant G-1307, British Heart Foundation (RG/13/5/30112), the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Compliance with ethical standards
Conflict of interest
The authors report no conflicts.
- 7.Vadgama N, Gaze D, Ranson J et al (2015) Elevated γ-glutamyltransferase and erythrocyte sedimentation rate in ischemic stroke in discordant monozygotic twin study. Int J Stroke 10:. https://doi.org/10.1111/ijs.12440
- 10.Walker HK, Hall WD, Hurst JW (1990) Clinical Methods. ButterworthsGoogle Scholar
- 26.Schiopu A, Cotoi OS (2013) S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators Inflamm 2013:828354. https://doi.org/10.1155/2013/828354
- 29.Yang Z, Bowles NE, Scherer SE et al (2006) Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Circ Res 99:646–655. https://doi.org/10.1161/01.RES.0000241482.19382.c6 CrossRefGoogle Scholar
- 32.Godyna S, Diaz-Ricart M, Argraves WS (1996) Fibulin-1 mediates platelet adhesion via a bridge of fibrinogen. Blood 88:2569–2577Google Scholar