Identification of Shared Molecular Signatures Indicate the Susceptibility of Endometriosis to Multiple Sclerosis

Amit Katiyar,Tej P Singh,Sujata Sharma,Punit Kaur

doi:10.3389/fgene.2018.00042

Amit Katiyar, Tej P Singh + Show 2 more

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https://doi.org/10.3389/fgene.2018.00042

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Abstract

Women with endometriosis (EMS) appear to be at a higher risk of developing other autoimmune diseases predominantly multiple sclerosis (MS). Though EMS and MS are evidently diverse in their phenotype, they are linked by a common autoimmune condition or immunodeficiency which could play a role in the expansion of endometriosis and possibly increase the risk of developing MS in women with EMS. However, the common molecular links connecting EMS with MS are still unclear. We conducted a meta-analysis of microarray experiments focused on EMS and MS with their respective controls. The GEO2R web application discovered a total of 711 and 1516 genes that are differentially expressed across the experimental conditions in EMS and MS, respectively with 129 shared DEGs between them. The functional enrichment analysis of DEGs predicts the shared gene expression signatures as well as the overlapping biological processes likely to infer the co-occurrence of EMS with MS. Network based meta-analysis unveiled six interaction networks/crosstalks through overlapping edges between commonly dysregulated pathways of EMS and MS. The PTPN1, ERBB3, and CDH1 were observed to be the highly ranked hub genes connected with disease-related genes of both EMS and MS. Androgen receptor (AR) and nuclear factor-kB p65 (RelA) were observed to be the most enriched transcription factor in the upstream of shared down-regulated and up-regulated genes, respectively. The two disease sample sets compared through crosstalk interactions between shared pathways revealed commonly up- and down-regulated expressions of 10 immunomodulatory proteins as probable linkers between EMS and MS. This study pinpoints the number of shared genes, pathways, protein kinases, and upstream regulators that may help in the development of biomarkers for diagnosis of MS and endometriosis at the same time through improved understanding of shared molecular signatures and crosstalk.

Highlights

Endometriosis (EMS) is an estrogen-dependent inflammatory disorder which affects approximately 5–10% of women in the reproductive age worldwide (Bulun, 2009)
Accessible gene expression datasets related to endometriosis (EMS) and multiple sclerosis (MS) were obtained from the Gene Expression Omnibus (GEO) database of national center for biotechnology information (NCBI)
The acquired differentially expressed genes (DEG) from this study were mapped to the validated disease genes of endometriosis and MS offered in Online Mendelian Inheritance in Man (OMIM) (Amberger et al, 2014) and DisGeNET (Piñero et al, 2015) human genetic disorder databases

Summary

Introduction

Endometriosis (EMS) is an estrogen-dependent inflammatory disorder which affects approximately 5–10% of women in the reproductive age worldwide (Bulun, 2009). The macrophages misinterpret the displaced ectopic endometrial tissue as an injury and instead of removing the endometrial cells, they activate pathways that repair and enhance their survival leading to sustained endometrial tissue (Podgaec et al, 2010; Capobianco and Rovere-Querini, 2013). T-helper 1 (Th1)/Thelper 2 (Th2) imbalance has been associated with both EMS and MS wherein the pro-inflammatory Th1 profile dominates over the Th2 anti-inflammatory response. This is similar to other autoimmune diseases where the immune system launches an attack on its own cells and tissues (Trapp et al, 1998; Peterson et al, 2001; Diestel et al, 2003; Aktas et al, 2005). An examination of possible crosstalks and shared components among common dysregulated pathways together with associated genes in both endometriosis and MS may be able to assist in the understanding of the disease mechanism

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