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4. Discussion

There are several signature genes that emerged from the Results chapter. This chapter will present a discussion of the findings, in particular the various gene functions and their relevant associations.

4.1 AD lesional

  • Nuclear Envelope Integral Membrane Protein 2, NEMP2, is a protein-coding gene1,2. Assessing the RNA expression data2 generated in the Human Protein Atlas (HPA) project, it may be speculated that NEMP2 potentially originates from endothelial and skin cell lines. Although NEMPs have not been widely studied in the literature, it has been indicated that a possible physiological function is a participation in the control of various neuropeptides secreted in the synaptic cleft1. Broadly, neuropeptides influence the activity of the brain, as well as the way the body functions3.

  • SOX21 Antisense Divergent Transcript 1, SOX21-AS1, is an RNA gene and it is affiliated with the long non-coding RNAs (lncRNA) class4 which are considered to be critical players in cancer progression5. Interestingly, the gene is dysregulated in several types of human cancer, including oral squamous cell carcinoma and colorectal cancer, and has been identified as a tumour facilitator6. In the literature7,8,9, there is evidence of the role AD plays in the development of keratinocyte malignancies, suggesting an elevated risk of patients developing cancer if a patient has a history of atopy-related diseases10 such as AD or asthma. This finding could be interesting for further investigation to strengthen the evidence of the association between AD and cancer.

  • Retinitis pigmentosa 11 - 775C24.5, RP11-775C24.5, broadly has been related to the development of colorectal cancer11 which is one of the most common types of cancer in terms of global mortality12. The correlation between AD and colorectal cancer is worth mentioning because it has been a matter of persistent scientific debate and there is evidence to suggest that having AD can potentially lead to the development of colorectal cancer13. Similar to SOX21-AS1, RP11-775C24.5 could be studied further to determine whether it is linked to AD, followed by an exploration of RP11-775C24.5 and its role in colorectal cancer.

  • Chromosome 5 Open Reading Frame 46, C5orf46, is a protein-coding gene14 which has been classified as one of the most prominent prognostic markers in renal and cervical cancer. For instance, patients with upregulated expression of C5orf46 have a 50% lower survival rate after ten years than patients with downregulated expression15. The study by Krueger et al16 (2019) confirms that C5orf46 is associated with various skin conditions and reports the gene in top 20-fold dysregulated genes in the LS skin transcriptome16. Furthermore, an earlier study by Gerber et.al17 (2013) found that C5orf46 was downregulated not only for AD but also PSO patients.

4.2 AD non-lesional

  • N-acylsphingosine amidohydrolase 1, ASAH1, encodes a member of the acid ceramidase family of proteins18. Early studies have identified that ASAH1 is upregulated after radiotherapy18, suggesting it plays a role in imparting radioresistance to glioblastoma, an aggressive type of cancer, and in the development of recurrent glioblastoma. Inhibiting the activity of ASAH1 through the use of targetted drugs has been used in the treatment of glioblastoma 19 and pediatric brain tumours20. ASAH1 has been found21,22 to be related to AD, confirming this results of this study.

  • Neuroepithelial cell-transforming 1, NET1, is a protein-coding gene that has been linked to malignancy in several cancer types23. There is also evidence24 suggesting that the gene plays a role in repairing DNA damage after ionising radiotherapy. NET1 has also been mentioned25 in relation to Attention-Deficit Hyperactivity Disorder (ADHD). There are no current studies assessing the role of NET1 in the context of AD. However, as described earlier for cancer-related genes, the gene can be potentially linked to AD but experimental data is required to validate this claim.

  • Long Intergenic Non-Protein Coding RNA 1431, LINC01431, is an RNA Gene and it is affiliated with the lncRNA class26. There is a limited number of studies that include this gene. In the study conducted by Panossian et al.27 (2018), the gene has been broadly linked to age-related diseases such as Alzheimer disease and senile dementia. It may be speculated, based on LINC01431's affiliation with the lncRNA class28, that this gene may be linked to AD.

4.3 PSO lesional

  • Zinc Finger and BTB Domain Containing 11, ZBTB11, is a protein-coding gene that may be involved in transcriptional regulation29. This gene has been linked to mental retardation30 and disease mutation31. ZBTB11 has been studied during keratinocyte differentiation32 and could be identified as a PSO-related gene.

  • LINC01431 has been discussed earlier for the AD lesional condition. There is no evidence in the literature, however, suggesting that the gene is linked to PSO.

  • Solute Carrier Family 6 Member 16, SLC6A16, is a protein-coding gene33 and the gene has been found to be a part of the Nrf2 pathway34. Nrf2 is a transcription factor which regulates cellular defences against a range of oxidative stresses35. The Nrf2 pathway promotes keratinocyte proliferation and contributes to the pathogenesis of PSO36. As there are no current studies that confirm the role of SLC6A16 in PSO, this signature gene should be considered for future research.

  • Serine/Threonine/Tyrosine Kinase 1, STYK1, is a protein-coding gene 37. According to Liu et al.38 (2014), the gene plays vital roles in cell proliferation, differentiation, and survival. STYK1 along with 282 other genes, is a part of the Focal Adhesion pathway, the importance of which has been stressed in the literature40. It is important to note, however, that there are no studies linking this gene to PSO.

4.4 PSO non-lesional

  • RP11-487I5.4 and RP11-332H18.3 are genes that have similar properties to RP11-775C24.5 that were discussed earlier. There are several studies validating that these genes play a role in the pathogenesis of PSO by regulating both microRNAs and genes41.

  • Phosphatidylinositol-glycan-specific phospholipase D, GPLD1, is a protein-coding gene42. It has been associated with several diseases, including glandular tularemia42. Interestingly, GPLD1 has been identified to participate in the phosphatidylcholine metabolic process with 60 other genes43. This metabolic process has been suggested to play a role in the psoriatic epidermis, potentially validating this candidate gene as being relevant to the disease.


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  4. Yang CM, Wang TH, Chen HC, Li SC, Lee MC, Liou HH, et al. Aberrant DNA hypermethylation-silenced SOX21-AS1 gene expression and its clinical importance in oral cancer. Clin Epigenetics. 2016; 8 :129. ↩

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  14. C5orf46 Gene - GeneCards [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=C5orf46 ↩

  15. Expression of C5orf46 in cancer - Summary - The Human Protein Atlas [Internet]. [cited 2020 Jun 17]. Available from: https://www.proteinatlas.org/ENSG00000178776-C5orf46/pathology ↩

  16. Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol. 2015 Feb 1; 135 (2):324–36. ↩↩

  17. Gerber PA, Hevezi P, Buhren BA, Martinez C, Schrumpf H, Gasis M, et al. Systematic Identification and Characterization of Novel Human Skin-Associated Genes Encoding Membrane and Secreted Proteins. PLoS One. 2013 Jun 20; 8 (6). ↩

  18. Doan NB, Nguyen HS, Al-Gizawiy MM, Mueller WM, Sabbadini RA, Rand SD, et al. Acid ceramidase confers radioresistance to glioblastoma cells. Oncol Rep. 2017 Oct 1; 38 (4):1932–40. ↩↩

  19. Doan NB, Alhajala H, Al-Gizawiy MM, Mueller WM, Rand SD, Connelly JM, et al. Acid ceramidase and its inhibitors: A de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency. Oncotarget. 2017; 8 (68):112662–74. ↩

  20. Doan NB, Nguyen HS, Montoure A, Al-Gizawiy MM, Mueller WM, Kurpad S, et al. Acid ceramidase is a novel drug target for pediatric brain tumors. Oncotarget. 2017; 8 (15):24753–61. ↩

  21. Sawada E, Yoshida N, Sugiura A, Imokawa G. Th1 cytokines accentuate but Th2 cytokines attenuate ceramide production in the stratum corneum of human epidermal equivalents: An implication for the disrupted barrier mechanism in atopic dermatitis. J Dermatol Sci. 2012 Oct 1; 68 (1):25–35. ↩

  22. Luo W, Xu W, Xia L, Xie D, Wang L, Guo Z, et al. Family-based whole exome sequencing of atopic dermatitis complicated with cataracts. Oncotarget. 2017; 8 (35):59446–54. ↩

  23. Sun H, Zhang Z, Luo W, Liu J, Lou Y, Xia S. NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells. Oncol Res. 2019 Aug 8; 27 (8):935–44. ↩

  24. NET1 Gene - GeneCards | ARHG8 Protein | ARHG8 Antibody [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=NET1&keywords=NET1 ↩

  25. Verlaet AAJ, Maasakkers CM, Hermans N, Savelkoul HFJ. Rationale for dietary antioxidant treatment of ADHD. Vol. 10, Nutrients. MDPI AG; 2018. p. 405. ↩

  26. LINC01431 Gene - GeneCards | LINC01431 RNA Gene [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=LINC01431&keywords=LINC01431 ↩

  27. Panossian A, Seo EJ, Efferth T. Synergy assessments of plant extracts used in the treatment of stress and aging-related disorders. Synergy. 2018 Dec 1; 7 :39–48. ↩

  28. Wang X, Bao K, Wu P, Yu X, Wang C, Ji L, et al. Integrative analysis of lncRNAs, miRNAs, and mRNA-associated ceRNA network in an atopic dermatitis recurrence model. Int J Mol Sci. 2018 Oct 20; 19 (10). ↩

  29. ZBTB11 Gene - GeneCards | ZBT11 Protein | ZBT11 Antibody [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZBTB11&keywords=ZBTB11 ↩

  30. Fattahi Z, Sheikh T, Musante L. Biallelic missense variants in ZBTB11 can cause intellectual disability in humans | Human Molecular Genetics | Oxford Academic. Hum Mol Genet [Internet]. 2018 Sep [cited 2020 Jun 17]; 27 (18):3177–88. Available from: https://academic.oup.com/hmg/article/27/18/3177/5034855 ↩

  31. ZBTB11 protein expression summary - The Human Protein Atlas [Internet]. [cited 2020 Jun 17]. Available from: https://www.proteinatlas.org/ENSG00000066422-ZBTB11 ↩

  32. Back SJ, Im M, Sohn KC, Choi DK, Shi G, Jeong NJ, et al. Epigenetic modulation of gene expression during keratinocyte differentiation. Ann Dermatol. 2012 Aug 1; 24 (3):261–6. ↩

  33. SLC6A16 Gene - GeneCards | S6A16 Protein | S6A16 Antibody [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC6A16&keywords=SLC6A16 ↩

  34. PathCards :: NRF2 pathway Pathway and related pathways [Internet]. [cited 2020 Jun 17]. Available from: https://pathcards.genecards.org/card/nrf2 ↩

  35. Yang L, Fan X, Cui T, Dang E, Wang G. Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17. J Invest Dermatol. 2017 Oct 1; 137 (10):2168–76. ↩

  36. Endo H, Sugioka Y, Nakagi Y, Saijo Y, Yoshida T. A novel role of the NRF2 transcription factor in the regulation of arsenite-mediated keratin 16 gene expression in human keratinocytes. Environ Health Perspect. 2008 Jul; 116 (7):873–9. ↩

  37. STYK1 Gene - GeneCards | STYK1 Protein | STYK1 Antibody [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=STYK1&keywords=STYK1 ↩

  38. Liu L, Yu XZ, Li TS, Song LX, Chen P La, Suo TL, et al. A novel protein tyrosine kinase NOK that shares homology with platelet-derived growth factor/fibroblast growth factor receptors induces tumorigenesis and metastasis in nude mice. Cancer Res. 2004 May 15; 64 (10):3491–9. ↩

  39. PathCards :: Focal Adhesion Pathway and related pathways [Internet]. [cited 2020 Jun 17]. Available from: https://pathcards.genecards.org/Card/focal_adhesion?queryString=STYK1 ↩

  40. Chen G, McCormick TS, Hammerberg C, Ryder-Diggs S, Stevens SR, Cooper KD. Basal keratinocytes from uninvolved psoriatic skin exhibit accelerated spreading and focal adhesion kinase responsiveness to fibronectin. J Invest Dermatol. 2001 Dec 1; 117 (6):1538–45. ↩

  41. Dolcino M, Pelosi A, Fiore PF, Patuzzo G, Tinazzi E, Lunardi C, et al. Long non-coding RNAs play a role in the pathogenesis of psoriatic arthritis by regulating microRNAs and genes involved in inflammation and metabolic syndrome. Front Immunol. 2018 Jul 16; 9 (JUL). ↩

  42. GPLD1 Gene - GeneCards | PHLD Protein | PHLD Antibody [Internet]. [cited 2020 Jun 17]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=GPLD1&keywords=GPLD1 ↩↩

  43. Gene Set - phosphatidylcholine metabolic process [Internet]. [cited 2020 Jun 17]. Available from: http://amp.pharm.mssm.edu/Harmonizome/gene_set/phosphatidylcholine+metabolic+process/GO+Biological+Process+Annotations ↩