Elevated γ-Glutamyltransferase and Erythrocyte Sedimentation Rate in Ischemic Stroke in Discordant Monozygotic Twin Study

Vadgama, Nirmal; Gaze, David; Ranson, Jacob; Hardy, John; Nasir, Jamal

doi:10.1111/ijs.12440

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“…Monozygotic (MZ) twins that are discordant with respect to a genetic disease offer a unique opportunity to explore the genetics of complex diseases [6]. We previously described a unique pair of then 57-year-old MZ twins discordant for IS with raised -glutamyl transferase (GGT) and erythrocyte sedimentation rate (ESR) in the affected twin [7]. Here, we describe proteomic analysis of serum samples from the twins.…”

Section: Introductionmentioning

confidence: 99%

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%