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

DISCUSSION

MS is an immune mediated chronic inflammatory demyelinating disease of CNS. While very little is known about the etiology of this disease, vitamin D as well as its receptor gene, VDR, are thought to be associated with MS. However, this is a controversial topic since there is disagreement in the literature. Therefore, we have evaluated the polymorphisms in the vitamin D receptor (VDR) among 271 MS patients and 203 healthy controls to determine if we observed any association with it and MS in the Turkish population. Our results showed a significant relationship in the Turkish population between VDR gene polymorphisms among MS or MS subtypes. This was true for two distinct (Fok-I and Taq-I) VDR gene polymorphisms. However, there was no significant relationship between VDR gene Bsm-I polymorphism with MS or MS subtypes in our study. Previous research evaluating the effect of exogenous vitamin D in prevention of MS development based on genetic tendency has helped to establish the importance of polymorphisms [22]. The Fok-I polymorphism is a T/C allele variation located in exon 2 which is in the translation initiation site of VDR. An interaction was observed between the dietary intake of vitamin D and the VDR Fok-I polymorphism and risk of MS. It was argued that vitamin D has a higher effect on MS prevention in women carrying the T allele [22]. Therefore, the determination of immune status by genetic predisposition, according to vitamin D intake, allowed for better assessment of MS risk [22]. However, there was no association between Fok-I polymorphisms on the VDR gene and MS in the Australian population [25]. In a separate study evaluating MS patients in the British population, there is a tendency for low VDR expression in people with the Fok-I polymorphism (T/T) genotype on the VDR gene. However, the relationship between MS and VDR single nucleotide polymorphisms has not been established, as results in the studies differ from each other [29]. Smolders et al. observed a relation between the Fok-I polymorphism in the VDR gene and the level of vitamin D. The C allele of the Fok-I polymorphism is associated with decreased 25(OH)D and increased 1,25-dihydroxyvitamin D (1,25(OH)D) levels [29]. Polymorphisms in the VDR gene were found to be associated with the severity and course of MS, as Mamutse et al. demonstrate that the Fok-I allele was associated with a decreased 10 year disability level, following initial disease development [30]. By contrast, a meta-analysis [22, 23, 25, 29, 31, 32] conducted on the Caucasian population indicates that the risk of MS is independent of Fok-I polymorphisms in dominant, heterozygote and recessive gene models [7]. Another study found that distribution of the VDR gene Fok-I polymorphisms was associated with MS in the Turkish population [33]. In a meta-analysis covering the research up to 2019, there was no association found between Fok-I polymorphisms and MS [34]. In our study, it was found that the Fok-I T/T polymorphism on the VDR gene in a dominant inheritance model and Fok-I T allele frequency were significantly associated with MS in Turkish population. The Bsm-I polymorphism is located in intron 8 of VDR and has a G/A variation. The first studies to report a relationship between MS and Bsm-I polymorphisms on the VDR gene were found in the Japanese population [14, 24]. However, it was later found that there was no association between Bsm-I polymorphisms on the VDR gene and MS in the Canadian population [35]. In the meta-analysis of studies up to 2019, there was no association between Bsm-I polymorphisms and MS, but when compared with the European population and the Asian population, there was an association between Bsm-I polymorphisms and MS [34]. In our study, it was found that there was no association between Bsm-I polymorphisms on the VDR gene and MS in the Turkish population. The Taq-I polymorphism is found at exon 9 of VDR with a C/T variation. An association was found between the Taq-I polymorphisms on the VDR gene and MS in the Australian population [25]. In contrast to this study, there was no association between the Taq-I polymorphisms and MS in the Canadian population [35]. A similar study found that there was no association between Taq-I polymorphisms on the VDR gene and MS in the Turkish population [33]. The aforementioned meta-analysis includes the research on this subject until 2019, and there was an association between Taq-I polymorphisms and MS only in the heterozygote model, but not in other inheritance models [34]. The results of our study showed that Taq-I C/C polymorphism on the VDR gene in dominant, homozygote and heterozygote inheritance models, and C allele frequency were significantly associated with MS in the Turkish population. In summary, we found that a significant relationship in the Turkish population exists between VDR gene polymorphisms (Fok-I, and Taq-I) and MS. A similar study among the Turkish population found an association between VDR gene Fok-I polymorphisms and MS. According to this study, however, there was no association between Taq-I VDR gene polymorphisms and MS. These data are important, since previous reports on this topic differ from one another, and more studies are needed. Some of the limitations of our study which should be considered include: small sample size and a different ethnicity, compared to other studies. These limitations might be the reason for the contradictions between our study and the study of Kamisli et al. among the Turkish population. Accordingly, our study adds further evidence to the argument that VDR is associated with MS, at least in certain populations. Acknowledgements This work was supported by the grant from The Marmara University Research Foundation. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Author Contributions BB: conducted the experiments and analyzed the data; HAY: conducted the experiments and developed the methodology; KSN: developed the methodology and provisioned the materials; CA: developed the methodology and provisioned the materials; CEA: provisioned the materials; IN: provisioned the materials; ELO: prepared the published work; AA: planned, executed the research and prepared the published work.



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