Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis

https://doi.org/10.1016/j.jneuroim.2008.12.011Get rights and content

Abstract

Multiple sclerosis (MS) has been associated with low levels of 25-hydroxyvitamin D (25(OH)D). Several genetic polymorphisms of the vitamin D receptor gene (VDRG), of whom Fok-I (rs10735810) has functional consequences for receptor protein structure and the immune system, have been studied in relation to MS with variable results. The purpose of our study was to assess an association of the Fok-I VDRG polymorphism with MS, and to further unravel the interaction of this polymorphism with vitamin D metabolism. Therefore, we genotyped 212 MS patients and 289 healthy controls for the Fok-I polymorphism and determined levels of the vitamin D metabolites 25(OH)D and 1,25(OH)2D. No association of the Fok-I VDRG polymorphism with MS was found. The F-allele was associated with lower winter and summer serum 25(OH)D levels in our MS patients, and with lower 25(OH)D levels in healthy controls. Remarkably, the F-allele corresponded with higher 1,25(OH)2D levels in MS patients. In all groups, carriers of the F-allele had higher 1,25(OH)2D/ 25(OH)D-ratios compared to their f-allele counterparts. In conclusion, we demonstrated the importance of the Fok-I VDRG polymorphism for vitamin D metabolism. This should be taken into account in association and ultimately intervention studies on vitamin D and MS.

Introduction

Limited vitamin D exposure is considered to be an environmental risk factor for developing multiple sclerosis (MS) (Smolders et al., 2008a). Twenty-five-hydroxyvitamin D (25(OH)D) is the principal vitamin D metabolite in serum, and is widely used to determine the vitamin D status of an individual (Hollis, 1996). Low serum levels of 25(OH)D in adolescence are associated with an increased risk of developing MS in a white American population (Munger et al., 2006). Limited sunlight exposure, the principal source of vitamin D synthesis, is associated with a high risk for MS in American, Tasmanian and Norwegian populations (Islam et al., 2007, Kampman et al., 2007, van der Mei et al., 2003). One of the genetic factors contributing to this risk, might be the genetic constitution of the vitamin D receptor (VDR), the receptor for the biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D).

The vitamin D receptor gene (VDRG) is located on chromosome 12q 12–14. Various single nucleotide polymorphisms (SNPs) in the VDRG have been described. The most frequently studied in MS are usually referred to by the names of the digestion enzymes used for genotyping. The polymorphisms Apa-I (rs7975232), Bsm-I (rs1544410) and Taq-I (rs731236) are located near the 3′ end, and the polymorphism Fok-I (rs10735810) near the 5′ end of the VDRG. The Fok-I polymorphism leads to a 3 amino-acids longer VDR protein by directly introducing a start codon. A functional impact of this polymorphism on the immune response has been demonstrated (Colin et al., 2000, van Etten et al., 2007). The biological consequences of the other polymorphisms are less certain.

Several studies have addressed the association of these VDRG polymorphisms with MS, with various results (Fukazawa et al., 1999, Niino et al., 2000, Partridge et al., 2004, Steckley et al., 2000, Tajouri et al., 2005, Yeo et al., 2004). Since the studies in which an association was reported were performed in a subtropical area with much sunlight (Tajouri et al., 2005), and an area where the diet contains large amounts of fat fish (Fukazawa et al., 1999, Niino et al., 2000), these populations were presumably exposed to relatively large environmental supplies of vitamin D. We hypothesized that an association of a VDRG polymorphism with MS might only be penetrant in a population with an adequate vitamin D exposition. We determined the VDRG polymorphism and 25(OH)D levels in patients and controls, in order to assess a possible association with selective inclusion of patients with an adequate vitamin D status. However, upon validation of this approach, there appeared a direct interaction of the polymorphism with vitamin D metabolism.

This study had several purposes. First of all, a possible association of the Fok-I VDRG polymorphism with MS was assessed in our population. Secondly, we investigated an association of the Fok-I polymorphism with 25(OH)D levels in a large population. In order to further evaluate the consequences of the polymorphism for vitamin D metabolism, we also assessed an association of the Fok-I VDRG polymorphism with serum levels of the biologically active metabolite of vitamin D, 1,25(OH)2D. To limit the effect of seasonal fluctuation of vitamin D photosynthesis, these associations were assessed both in summer and in winter period.

Section snippets

Population

Two-hundred and twelve patients with clinically and MRI-confirmed MS (McDonald et al., 2001) and 289 healthy community controls were included in this study, after informed consent was acquired. The population characteristics are shown in Table 1. Patients and controls all lived in the southern part of the Netherlands (latitude 50° N–51° N). This project was approved by the local medical ethics committee.

Clinical and biochemical parameters

Blood samples of our MS patients were collected in summer (from May to October) and winter

No association of Fok-I VDR genotype with MS

The genotype and allele-frequencies of the Fok-I VDRG polymorphism in the whole MS and control cohorts are described in Table 2. Both cohorts were in Hardy–Weinberg equilibrium. There was no difference in the distribution of genotypes or alleles between patients and controls.

Next, we intended to identify a possible association between the Fok-I VDRG polymorphism and MS by selective inclusion of patients with an adequate vitamin D status. However, since a possible association between 25(OH)D

Discussion

This is the first study to asses serum levels of 25(OH)D and 1,25(OH)2D, and the Fok-I VDRG polymorphism in two unrelated large cohorts of MS patients and healthy controls. Firstly, we did not find an association of the Fok-I VDRG polymorphism with MS in our population. Secondly, we observed an association of the F allele with low 25(OH)D levels in patients and controls. Thirdly, we extended these findings in our MS cohort by showing a reverse association of the F allele with high summer

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. We thank Dr. Mariëlle Thewissen and Evelyn Peelen for the useful discussions, Bertine Timmermans and Riny Wieërs for their help with collecting the vitamin D data, and Ruud Theunissen for his skilled technical assistance.

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      In addition, previous studies revealed that FF genotype was related to the efficient of basal transcription factor IIB, and as a result, it led to higher transcriptional activity of VDR (Jurutka et al., 2000; Whitfield et al., 2001) and has the greater risk for stone formation (Liu et al., 2007). Furthermore, studies (Smolders et al., 2009; Tanabe et al., 2015) had also reported that FF genotype of VDR Fok-I gene polymorphism was observed significantly correlating to elevated serum level of 1,25(OH)2D and 25(OH)D. While, increased circulating 1,25(OH)2D and elevated level of 25(OH)D are significantly associated with hypercalciuria (Hu et al., 2017) and urinary calcium excretion (Kim et al., 2014). These feasible mechanisms might elucidate our results.

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