Gene Co-expression Network Analysis for Identifying Modules and Functionally Enriched Pathways in Vitiligo Disease: A Systems Biology Study

The key gene modules in Vitiligo disease

  • Afshin Derakhshani ORCID Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  • Homa Mollaei ORCID Department of Biology, Faculty of Sciences, University of Birjand, Birjand, Iran
  • Negin Parsamanesh ORCID Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
  • Mohammad Fereidouni ORCID Cellular and Molecular Research center, Birjand University of Medical Sciences, Birjand, Iran
  • Ebrahim Miri-Moghaddam ORCID Department of Molecular Medicine, Cardiovascular Diseases Research Center, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
  • Saeed Nasseri ORCID Cellular and Molecular Research center, Birjand University of Medical Sciences, Birjand, Iran
  • Yongwen Luo ORCID Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
  • Hossein Safarpour ORCID 4 Cellular and Molecular Research center, Birjand University of Medical Sciences, Birjand, Iran
  • Behzad Baradaran ORCID Mail Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran AND Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
MicroRNAs, Systems biology, Vitiligo


Vitiligo is the most common cause of skin, hair, and oral depigmentation which is known as an autoimmune disorder. Genetic and environmental factors have important roles in the progression of the disease. Dysregulation of gene expression, like microRNAs (miRNA), may serve as major relevant factors. Several biological processes are involved in vitiligo disease and developing a comprehensive approach helps us to better understand the molecular mechanisms of disease.
In this research, we describe how a weighted gene co-expression network analysis as a systems biology approach assists to define the primary gene modules, hub genes, and messenger RNA (mRNA)-miRNA regulatory network in vitiligo disease as the novel biomarkers.
The results demonstrated a module with a high correlation with vitiligo state. Moreover, gene enrichment analysis showed that this module's genes were mostly involved in some biological activities including G protein-coupled receptors signaling pathway, lymphocyte chemotaxis, chemokine activity, neutrophil migration, granulocyte chemotaxis, etc. The co-expression network was constructed using top hub genes of the correlated module which are named as CXCL10, ARL9, AKR1B10, COX7B, RPL26, SPA17, NDUFAF2, RPF2, DAPL1, RPL34, CWC15, NDUFB3, RPL26L1, ACOT13, HSPB11, and NSA2. MicroRNAs prediction tool (miRWalk) revealed top miRNAs correlated with the interested module. Finally, a drug-target network was constructed which indicated interactions of some food and drug administration (FDA) approved drugs with hub genes.
Our findings specified one important module and main hub genes which can be considered as novel biomarkers for vitiligo therapeutic purposes.


1. Spritz RA. The genetics of generalized vitiligo and associated autoimmune diseases. Pigment Cell Res. 2007;20(4):271-8.
2. Jadali Z, Eslami MB, Sanati MH, Mansoori P, Mahmoudi M, Maghsoodi N, et al. Identification of hitherto undefined B-cell epitopes by antibodies in the sera of vitiligo patients using phage-display peptide library. Iran J Allergy Asthma Immunol. 2003;2(4):197-201.
3. Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CC, et al. Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012;25(3):E1-13.
4. Silverberg NB. The Epidemiology of Vitiligo. Curr Dermatol Rep. 2015;4(1):36-43.
5. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol. 2013;25(6):676-82.
6. Zhao Y, Srivastava D. A developmental view of microRNA function. Trends Biochem Sci. 2007;32(4):189-97.
7. Rezaei Z, Sebzari A, Kordi-Tamandani DM, Dastjerdi KJD, biology c. Involvement of the Dysregulation of miR-23b-3p, miR-195-5p, miR-656-5p, and miR-340-5p in Trastuzumab Resistance of HER2-Positive Breast Cancer Cells and System Biology Approach to Predict Their Targets Involved in Resistance. 2019;38(2):184-92.
8. Rebane A, Akdis CA. MicroRNAs: Essential players in the regulation of inflammation. J Allergy Clin Immunol. 2013;132(1):15-26.
9. Sonkoly E, Wei T, Janson PC, Saaf A, Lundeberg L, Tengvall-Linder M, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One. 2007;2(7):e610.
10. Rebane A, Runnel T, Aab A, Maslovskaja J, Rückert B, Zimmermann M, et al. MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. J Allergy Clin Immunol. 2014;134(4):836-47.
11. Vennegaard MT, Bonefeld CM, Hagedorn PH, Bangsgaard N, Lovendorf MB, Odum N, et al. Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice. Contact Derm. 2012;67(5):298-305.
12. Shi YL, Weiland M, Lim HW, Mi QS, Zhou L. Serum mi RNA expression profiles change in autoimmune vitiligo in mice. Exp Dermatol. 2014;23(2):140-2.
13. Wang Y, Wang K, Liang J, Yang H, Dang N, Yang X, et al. Differential expression analysis of mi RNA in peripheral blood mononuclear cells of patients with non‐segmental vitiligo. Int J Dermatol. 2015;42(2):193-7.
15. Cao W, Wu W, Yan M, Tian F, Ma C, Zhang Q, et al. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma. Oncogenesis. 2015;4(11):e175.
16. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16(2):90-100.
17. van den Boorn JG, Konijnenberg D, Dellemijn TA, van der Veen JP, Bos JD, Melief CJ, et al. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. The Journal of investigative dermatology. 2009;129(9):2220-32.
18. Ahmadloo S, Taghizadeh M, Akhiani M, Salimzadeh A, Keramatipour M. Single Nucleotide Polymorphism rs 2476601 of PTPN22 Gene and Susceptibility to Rheumatoid Arthritis in Iranian Population. Iran J Allergy Asthma Immunol. 2015;14(4):437-42.
19. Santamaria P. Cytokines and chemokines in autoimmune disease: an overview. Adv Exp Med Biol. 2003;520:1-7.
20. Arimilli S, Ferlin W, Solvason N, Deshpande S, Howard M, Mocci S. Chemokines in autoimmune diseases. Immunological reviews. 2000;177:43-51.
21. Khan U, Ghazanfar H. T Lymphocytes and Autoimmunity. International review of cell and molecular biology. 2018;341:125-68.
22. Antonelli A, Ferrari SM, Fallahi P. The role of the Th1 chemokine CXCL10 in vitiligo. Annals of translational medicine. 2015;3(Suppl 1):S16.
23. Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (Review). Oncol Lett. 2011;2(4):583-9.
24. Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su MW, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014;6(223):223ra23.
25. Ogg GS, Rod Dunbar P, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med. 1998;188(6):1203-8.
26. Yang L, Yang S, Lei J, Hu W, Chen R, Lin F, et al. Role of chemokines and the corresponding receptors in vitiligo: A pilot study. J Dermatol. 2018;45(1):31-8.
27. Van Vollenhoven RF, McGuire JL. Estrogen, progesterone, and testosterone: can they be used to treat autoimmune diseases? Cleve Clin J Med. 1994;61(4):276-84.
28. Vendramini AC, Soo C, Sullivan DA. Testosterone-induced suppression of autoimmune disease in lacrimal tissue of a mouse model (NZB/NZW F1) of Sjogren's syndrome. Invest Ophthalmol Vis Sci. 1991;32(11):3002-6.
29. Muto M, Furumoto H, Ohmura A, Asagami C. Successful treatment of vitiligo with a sex steroid-thyroid hormone mixture. J Dermatol. 1995;22(10):770-2.
30. Li C, Ge M, Yin Y, Luo M, Chen D. Silencing expression of ribosomal protein L26 and L29 by RNA interfering inhibits proliferation of human pancreatic cancer PANC-1 cells. Mol Cell Biochem. 2012;370(1-2):127-39.
31. Kwon DN, Park WJ, Choi YJ, Gurunathan S, Kim JH. Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss. Aging. 2015;7(8):579-94.
32. Laddha NC, Chatterjee S, Gani AR, Malek RA, Shah BJ, Begum R. Association of catalase T/C exon 9 and glutathione peroxidase codon 200 polymorphisms in relation to their activities and oxidative stress with vitiligo susceptibility in Gujarat population. Pigment Cell Res. 2007;20(5):405-7.
33. Schallreuter KU, Rubsam K, Gibbons NC, Maitland DJ, Chavan B, Zothner C, et al. Methionine sulfoxide reductases A and B are deactivated by hydrogen peroxide (H2O2) in the epidermis of patients with vitiligo. J Invest Dermatol 2008;128(4):808-15.
34. Moretti S, Fabbri P, Baroni G, Berti S, Bani D, Berti E, et al. Keratinocyte dysfunction in vitiligo epidermis: cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol. 2009;24(7):849-57.
35. Bishnoi A, Parsad D. Clinical and Molecular Aspects of Vitiligo Treatments. Int J Mol Sci. 2018;19(5).
36. Rashighi M, Harris JE. Vitiligo Pathogenesis and Emerging Treatments. Dermatol Clin 2017;35(2):257-65.
37. Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxid Med Cell Longev. 2015;2015:631927.
38. Shang Z, Li H. Altered expression of four miRNA (miR-1238-3p, miR-202-3p, miR-630 and miR-766-3p) and their potential targets in peripheral blood from vitiligo patients. J Dermatol. 2017;44(10):1138-44.
39. McDonald MK, Ramanathan S, Touati A, Zhou Y, Thanawala RU, Alexander GM, et al. Regulation of proinflammatory genes by the circulating microRNA hsa-miR-939. Sci Rep. 2016;6:30976.
How to Cite
Derakhshani A, Mollaei H, Parsamanesh N, Fereidouni M, Miri-Moghaddam E, Nasseri S, Luo Y, Safarpour H, Baradaran B. Gene Co-expression Network Analysis for Identifying Modules and Functionally Enriched Pathways in Vitiligo Disease: A Systems Biology Study. Iran J Allergy Asthma Immunol. 19(5):517-528.
Original Article(s)