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Identification of perturbed pathways rendering susceptibility to tuberculosis in type 2 diabetes mellitus patients using BioNSi simulation of integrated networks of implicated human genes

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Abstract

In type 2 diabetes mellitus (T2DM) patients, chronic hyperglycemia and inflammation underlie susceptibility to tuberculosis (TB) and result in poor TB control. Here, an integrative pathway-based approach is used to investigate perturbed pathways in T2DM patients that render susceptibility to TB. We obtained 36 genes implicated in type 2 diabetes-associated tuberculosis (T2DMTB) from the literature. Gene expression analysis on T2DM patient data (GSE26168) showed that DEFA1 is differentially expressed at Padj<0.05. The human host TB susceptibility genes TNFRSF10A, MSRA, GPR148, SLC37A3, PXK, PROK2, REV3L, PGM1, HIST3H2A, PLAC4, LETM2, and EMP2 and hsa-miR-146a microRNA were also differentially expressed at Padj<0.05. We included all these genes and added the remaining 28 genes from the T2DMTB set and the remaining differentially expressed genes at Padj<0.05 in STRING and obtained a well-connected network with high confidence score (≥0.7). Further, we extracted the KEGG pathways at FDR<0.05 and retained only the diabetes and TB pathways. The network was simulated with BioNSi using gene expression data. It is evident from BioNSi analysis that the NF-kappa B and Toll-like receptor pathways are commonly perturbed with high ranking in multiple gene expression datasets of type 2 diabetes versus healthy controls. The other pathways, necroptosis pathway and FoxO signalling pathway, appear perturbed with high ranking in different gene expression datasets. These pathways likely underlie susceptibility to TB in T2DM patients.

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Acknowledgements

We thank our lab members for their useful feedback. JR acknowledges ICMR (Indian Council of Medical Research) for Senior Research Fellowship (File No. BIC/11 (21)/2015). SR’s work is supported in part by a grant from ICMR (No. BIC/5 (09)/Indo-Russian/2016).

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Authors and Affiliations

  1. Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, New Delhi, 110019, India

    Jyoti Rani & Urmi Bajpai

  2. Informatics and Big Data, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, 110025, India

    Jyoti Rani, Anasuya Bhargav, Surabhi Seth & Srinivasan Ramachandran

  3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Anasuya Bhargav, Surabhi Seth, Malabika Datta & Srinivasan Ramachandran

  4. Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, 110007, India

    Malabika Datta

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  1. Jyoti Rani
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Correspondence to Srinivasan Ramachandran.

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Corresponding editor: Umesh Varshney

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Rani, J., Bhargav, A., Seth, S. et al. Identification of perturbed pathways rendering susceptibility to tuberculosis in type 2 diabetes mellitus patients using BioNSi simulation of integrated networks of implicated human genes. J Biosci 47, 69 (2022). https://doi.org/10.1007/s12038-022-00309-z

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