Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians
Introduction
MS risk is determined by gene–environment interaction and the association of higher MS prevalence in areas of lower ultra violet radiation (UVR) is well known [1]. The gradient of increasing MS risk with increasing latitude in both hemispheres parallels that for UVR distribution. The mechanism for the putative protective effect of UVR on MS risk is unclear but vitamin D remains the best candidate for mediating this effect [2]. Clinical observations consistent with this hypothesis include low serum concentrations of 25-hydroxyvitamin D [25(OH)D] in MS patients [3], [4], seasonal fluctuation in the timing of MS births [5], [6] and fluctuation in MS disease activity correlating with 25(OH)D seasonality [7]. Vitamin supplementation [8] and higher serum 25(OH)D concentrations in adulthood [9] were associated with reduced risk of MS in 2 US cohort studies. In addition, sunlight exposure through outdoor activity has shown an inverse correlation with MS susceptibility [10], [11], [12].
Accordingly, genes involved in Vitamin D metabolism and transport are potential candidates for affecting susceptibility to MS. The major genetic loci for MS susceptibility lie within the major histocompatibility complex (MHC), namely the HLA-DRB1*15 haplotype. HLA-DRB1 contains a vitamin D response element (VDRE) in its promoter region, which was shown to be completely conserved in the HLA-DRB1*15 promoter, as well as functional in vitro [13]. It is possible that variants in vitamin D receptor genes affect MS susceptibility indirectly by altering interaction at VDREs within the MHC regulatory region.
Vitamin D is transported in the circulation bound to proteins, ~ 88% of which are vitamin D binding proteins (DBP). It is then hydroxylated to 25-hydroxy-vitamin D [25(OH)D] in the liver. 25(OH)D is the main circulating metabolite of vitamin D and widely accepted as the best measure of vitamin D adequacy [14]. The rate limiting step in the activation of vitamin D is a second hydroxylation to 1,25-dihydroxyvitamin D (1,25(OH)2D) by cytochrome P450 enzymes, 1-alpha-hydroxylase (CYP27B1; [15], [16]). 24-hydroxylase enzymes (CYP24A1) degrade the active metabolite. Biological effects are exerted through 1,25(OH)2D binding to the VDR to alter gene expression in target genes [17]. The VDR-bound 1,25(OH)2D complex acts as a transcription factor to initiate gene transcription upon binding to VDREs[18]. Here we assessed common variants in the genes known to be responsible for these metabolic steps as potential candidates for influencing MS pathogenesis via their effect on vitamin D status.
The association of vitamin D-related genes and MS susceptibility has been previously studied. The findings are inconsistent, with some positive associations [19], [20], [21], [22], [23] and some negative or inconclusive ones [24], [25], [26], [27]. This inconsistency may in part be due to population stratification and in some cases insufficiently large sample sizes. Furthermore, many published studies are limited by lack of comprehensive gene coverage, many examining only the 4 RFLPs of the large VDR gene or a few select SNPs.
In addition to associations with MS susceptibility, these four genes have been studied with respect to regulation of serum 25(OH)D levels. Several studies have found that polymorphisms in VDR [22], [28], [29], CYP27B1 [28] and DBP [30] influence circulating 25(OH)D levels. Elucidating the potential role of vitamin D in MS etiology remains an attractive goal, as maintaining vitamin D sufficiency in populations at risk would be a straightforward and cost-effective target for intervention [31].
Section snippets
Subjects
All subjects used in the study were ascertained through the ongoing Canadian Collaborative Project on the Genetic Susceptibility to MS (CCPGSMS, [32]). Informed consent was obtained from all subjects and experiments performed for this investigation comply with current ethics and guidelines. A family-based approach was used to test for association of candidate genes and susceptibility. The dataset used comprised 739 families, consisting of sibling pair, parent–child, aunt–uncle–niece–nephew, and
Results
Seventy-one variants were genotyped in the dataset which included of 739 families consisting of 3037 individuals. All informative SNPs were analyzed for association with MS risk using PLINK (Table 1). Evidence for significant uneven transmission was observed in several VDR SNPs (rs1544410-Bsm1, rs11574077, rs12581281, rs3782905, rs3819545, rs757343), one CYP24A1 SNP (rs2244719), and one DBP SNP (rs1352845). However the positive findings all fell below the significance threshold after applying a
Discussion
MS results from the interplay of genetic and environmental factors, and compromised vitamin D status remains one of the most attractive proposed environmental factors [31]. Given the epidemiological and now genetic evidence, we have examined by a candidate gene approach those genes involved in the vitamin D endocrine system. Here we evaluated roles for CYP27B1, VDR, DBP, and CYP24A1 genetic variation in susceptibility to MS. Recent studies have shown that serum 25(OH)D levels are under genetic
Acknowledgments
SMO is funded by a Clarendon fund studentship. The MS Society of Canada Scientific Research Foundation funds the CCPGSMS.
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