by Saik Olga | Klimontov Vadim | RICEL – Branch of IC&G SB RAS | RICEL – Branch of IC&G SB RAS
Background: High glucose variability (GV) is recognized as a contributor for diabetic
microvascular and macrovascular complications, including diabetic retinopathy, chronic
kidney disease, diabetic neuropathy, and macrovascular disease. The results of numerous
studies have pointed to the role of endothelial dysfunction in the development of these
complications.
The aim: to identify genes linking GV with endothelial dysfunction in diabetes.
Methods: The gene networks reconstruction and analysis were performed by the
ANDSystem (www-bionet.sscc.ru/and/cell/).
Results: Sixty genes related to GV and endothelial dysfunction were found. The probability
of observing so many common genes for random reasons is very small (p-value<10-47). The
identified genes/proteins are involved in the activation, apoptosis, development,
differentiation, migration, morphogenesis and proliferation of endothelial cells. It was found
that in the GV gene network many genes associated with endothelial dysfunction have
relatively high values of betweenness centrality. The average of betweenness centrality
values for the common 60 genes involved in endothelial dysfunction and GV was 536, while
for all GV genes it was only 270. The difference of the betweenness centrality values for
these two gene sets is statistically significant (P-value=10-5, Mann-Whitney U test). All the
top ten genes with highest betweenness centrality values in the GV gene network (INS, IL6,
TP53, FOXO1, LEP, MAPK14, TNF, IL1B, IGF1, and VEGFA) were also involved in the
endothelial dysfunction.
Conclusions: Discovering the key genes involved both in the GV and endothelial
dysfunction could shed light on understanding of the pathogenesis of diabetes complications
and could support the future drug development.
This work was supported by the grant of Russian Science Foundation
(20-15-00057).