Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

Abstract

Background and Purpose: 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 welldocumented, 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. Methods: 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. Results: 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. 3 Conclusion: The identification of cellular pathways enriched in IS as well as the up-regulation 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.

Multi-scale systems genomics analysis predicts pathways, cell types and drug targets involved in normative human cognition variation

“…Multiple lines of evidence suggest that FBLN1 , the gene associated with genome-wide significant SNPs for nonverbal reasoning, is dysregulated in disease. In addition to the evidence provided in our results (Figure 1d, Figure 2c, Supplementary Figure 8,9), FBLN1 has been associated with other rare genetic syndromes and protein levels of FBLN1 have been associated with altered risk for ischaemic stroke 59,60 . However, the mechanism by which FBLN1 contributes to normal brain function is not known.…”

Quantitative proteomic analysis identified differentially expressed proteins with tail/rump fat deposition in Chinese thin- and fat-tailed lambs

“…Gene Ontology (GO) enrichment analysis of DEPs was implemented using g:Profiler (http:// biit.cs.ut.ee/gprofiler/) as described previously [39], and all the 3,400 proteins detected in the five samples were chosen as the background proteins. Protein classification was performed based on their functional annotations.…”