Investigation of RORA Gene Expression in Iranian Multiple Sclerosis (MS) Patients

Subject Areas : Journal of Animal Biology

Sakineh Nayeri ¹ , Arezoo Sayad ² , Vida Hojati ³ , Mohammad Taheri ⁴

1 - Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
2 - Department of Medical Genetics, Shahid Beheshti University, Tehran, Iran
3 - Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
4 - Department of Medical Genetics, Shahid Beheshti University, Tehran, Iran

Received: 2018-02-19 Accepted : 2018-02-19 Published : 2017-11-22

Keywords: Gene expression, Multiple Sclerosis, RORA,

Abstract :

Multiple sclerosis (MS) is one of the most important autoimmune diseases targeting central nervous system (OMIM: 126200). It is known to be the second factor of movement disability in the world which is increasing in recent years. It is essential to perform fundamental and functional studies on its prevention and treatment. Although the major causes of MS incidence are still unclear, CD4 (+) myelin-specific T cells play central role in generation and inflammation balance. Accordingly, activated CD4 (+) T cells in peripheral, penetrate into the CNS and trigger the inflammation cascade by inducing secretion of cytokine and chemokine. Among Th17 cells, one of CD4 (+) T cell lines is recently shown to be mainly involved in MS incidence. The role of RORA gene in the developmental pathways Th17 cells, and regarding evidence suggesting RORA receptors as potential treatment targets respecting inflammation disorders such as MS. Study on this gene would help us to discover the molecular causes of MS. We selected 30 individuals affected with MS and 30 healthy normal controls matched in gender and age. After filling a questionnaire, peripheral blood was obtained and total RNA was extracted by GeneAll kit. Then, cDNA was synthesized using GeneAll cDNA synthetize kit. Expression of RORA gene was investigated using TaqMan Real-Time PCR. Results were analyzed using Linreg and Rest 2009 software. Expression of RORA gene was not significantly reduced compared to controls (P=0.197). Moreover, expression of RORA gene was not significantly different between genders (P=0.142, P=0.156). There was no significant difference in RORA gene expression between cases and control group. Expression level of RORA gene may have not important effect on the disease.

References:

1. Bettelli E., Carrier Y., Gao W., Korn T., Storm T.B., Oukka M., Weiner H.L., Kuchroo V.K., 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235-238.


2. Bi Y., Liu G., Yang R., 2007. Th17 cell induction and immune regulatory effects. Journal of Cellular Physiology, 211: 273-278.


3. Chen Z., Laurence A., O'shea J.J., 2007. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation.  Seminars in Immunology, 2007: 400-408.


4. Chen Z., O’shea J.J., 2008. Th17 cells: a new fate for differentiating helper T cells. Immunologic research, 41: 87-102.


5. Dzhagalov I., Giguere V., He Y.W., 2004. Lymphocyte development and function in the absence of retinoic acid-related orphan receptor α. The Journal of Immunology, 173: 2952-2959.


6. Haerian B.S., Shaari H.M., Tan H.J., Fong C.Y., Wong S.W., Ong L.C., Raymond A.A., Tan C.T., Mohamed Z., 2015. RORA gene rs12912233 and rs880626 polymorphisms and their interaction with SCN1A rs3812718 in the risk of epilepsy: A case–control study in Malaysia. Genomics, 105: 229-236.


7. Hennings J., Uhr M., Klengel T., Weber P., Putz B., Touma C., Czamara D., Ising M., Holsboer F., Lucae S., 2015. RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response. Translational Psychiatry, 5: e538.


8. Ivanov I.I., Mckenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R., 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, 126: 1121-1133.


9. Jetten A.M., 2009. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nuclear Receptor Signaling, 7:e003.


10.  Kano H., Takayama T., Midorikawa Y., Nagase H., 2016. Promoter hypomethylation of RAR-related orphan receptor α 1 is correlated with unfavorable clinicopathological features in patients with colorectal cancer. BioScience Trends, 10(3): 202-209.


11.  Khaiboullina S.F., Gumerova A.R., Khafizova I.F., Martynova E.V., Lombardi V.C., Bellusci S., Rizanov A.A., 2015. CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis. BioMed Research International, 2015: 1-10,


12.  Kojetin D.J., Burris T.P., 2014. REV-ERB and ROR nuclear receptors as drug targets. Nature Reviews of Drug Discovery, 13: 197-216.


13.  Leppkes M., Becker C., Ivanov I.I., Hirth S., Wirtz S., Neufert C., Pouly S., Murphy A.J., Valenzuela D.M., Yancopoulos G.D., 2009. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology, 136: 257-267.


14.  Logue M.W., Baldwin C., Guffanti G., Melista E., Wolf E.J., Reardon A.F., Uddin M., Wildman D., Galea S., Koenen K.C., 2013. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Molecular Psychiatry, 18: 937-942.


15.  Rostami A., Ciric B., 2013. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. Journal of the Neurological Sciences, 333: 76-87.


16.  Sadeghi H., Gupta Y., Möller S., Samavedam U.K., Behnen M., Kasprick A., Bieber K., Muller S., Kalies K., De Castro Marques A., 2015. The retinoid‐related orphan receptor alpha is essential for the end‐stage effector phase of experimental epidermolysis bullosa acquisita. The Journal of Pathology, 237: 111-122


17. Yang X.O., Pappu B.P., Nurieva R., Akimzhanov A., Kang H.S., Chung Y., Ma L., Shab B., Panopoulos A.D., Schluns K.S., 2008. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity, 28: 29-39.


18.  Yin S., 2012. Gait Analysis of Multiple Sclerosis Patients. MSc Thesis, Arizona State University.

17.               Veldhoen M., Hocking R.J., Atkins C.J., Locksley R.M., Stockinger B., 2006. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity, 24: 179-189.