Balkan Journal of Medical Genetics

VITAMIN D RECEPTOR POLYMORPHISMS AMONG THE TURKISH POPULATION ARE ASSOCIATED WITH MULTIPLE SCLEROSIS
Bulan B1, Hoscan AY1, Keskin SN1, Cavus A1, Culcu EA1, Isik N2, List EO2, Arman A*4
*Corresponding Author: Dr. Ahmet Arman, The Department of Medical Genetics, Marmara Teaching and Research Hospital, Marmara University, 34899, Pendik, Istanbul/TURKEY. Tel #: +90-216- 657 0606, Fax #: +90-216-414 47 31, e-mail: ahmetarman@marmara.edu.tr, ORCID Id: https://orcid.org/0000-0001-5547-0024
page: 10

INTRODUCTION

Multiple Sclerosis (MS) is a chronic inflammatory disease which leads to demyelination and neurodegeneration of the central nervous system(CNS) [1, 2]. The disease generally affects young adults and causes serious neurological disabilities [3, 4]. Focal demyelination, inflammation, scar formation, and various axonal degeneration are involved in the pathology of MS lesions [4, 5, 6]. Axonal degeneration is the main reason for this non-reversible disability in MS patients [7]. While the etiology of MS is not fully understood, environmental, genetic, and geographical factors may play a part [7, 8, 9]. Specific environmental/metabolic factors including, Epstein Barr virus, seasonality in MS patients’ birth, sun exposure, vitamin D levels, and cigarettes have been shown to influence epidemiologic patterns in MS [10, 11]. The differences in susceptibility to MS, despite the same environmental exposures, indicates the involvement of genetic factors in the development of pathogenesis [7]. In recent years, genetic studies suggest that a single susceptible locus is not sufficient to lead to MS and that MS is a heterogeneous disease [12, 13]. Therefore, it is likely that multiple gene mutations are needed to contribute additively to the course of this disease [14]. In major gene regions, most of the loci associated with MS susceptibility are located at the major histocompatibility complex (MHC) which is also called the HLA-DRB1*15 haplotype. The promoter region of HLA-DRB1 gene contains a vitamin D response element (VDRE) which is important for gene expression of HLADRB1. Variants in the vitamin D receptor (VDR) gene affect MS susceptibility by the way of changing the interaction of VDRE on the MHC regulatory region [15]. Thus, vitamin D may play an important role in developing MS. Furthermore, vitamin D has been shown to impact immunomodulation in the MS pathogenesis [11, 16, 17]. The usage of the active form of vitamin D in experimental MS and experimental autoimmune encephalomyelitis (EAE) animal studies was shown to be beneficial [11, 18, 19]. Additionally, studies in mice indicate that the VDR gene has a critical role in EAE activity [20]. These findings suggest that VDR and its ligand have immunosuppressive and anti-inflammatory properties which affect MS susceptibility [1, 21]. Finally, there is an inverse correlation between vitamin D blood levels and MS prevalence [11]. Taken together, these studies indicate that vitamin D (or lack thereof) may play an important role in the development of MS. In addition to vitamin D, the vitamin D receptor (VDR) is hypothesized as playing a role in MS; however, this is a controversial topic. Various single nucleotide polymorphisms (SNP) including Apa-I (rs7975232), Bsm-I (rs1544410), Fok-I (rs2228570), and Taq-I (rs731236) in the VDR gene have been investigated for MS susceptibility, and are they thought to be associated with the MS disease [7, 21]. However, these results are inconclusive and there is disagreement among these findings [7, 22]. Several studies indicate that the VDR gene polymorphisms are associated with susceptibility to MS [23, 24, 25]. Furthermore, these polymorphisms in the VDR gene may change the vitamin D serum levels, vitamin D structure, and function as such with an immune modulatory effect; these are the mechanisms of the vitamin D and VDR complex [22]. By contrast, several studies suggest that these polymorphisms are not associated with MS as indicated by VDR-mRNA expression or active vitamin D induced target gene expression [7, 26]. Since there is disagreement in the literature, the aim of the current study was to investigate the relationship between the VDR Fok-I (rs2228570) T/C, Bsm-I (rs1544410) G/A, Taq-I (rs731236) T/C polymorphisms and MS disease in the Turkish population.

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