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Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS) risk is determined by both genes and environment. One of the most striking features of MS is its geographic distribution, particularly the pattern of high MS frequency in areas with low sunlight exposure, the main inducer of vitamin D synthesis. Recent epidemiologic, experimental, and clinical evidence support an effect for low environmental supplies of vitamin D in mediating an increased susceptibility to MS.We 1) examined the association of serum 25-hydroxy-vitaminD [25(OH)D] concentrations and MS status and 2) assessed the genetic contribution to serum 25(OH)D concentrations and tested for its association with genetic variants in 2 candidate genes [vitamin D receptor and 1-alpha-hydroxylase (CYP27B1)].We used a twin study approach, comprising adult pairs identified from the longitudinal population-based Canadian Collaborative Project on Genetic Susceptibility to MS. Monozygotic (MZ; n = 40) and dizygotic (DZ; n = 59) pairs, both concordant and discordant for MS, were studied. End-of-winter serum 25(OH)D concentrations were measured by radioimmunoassay, and genotypes were assessed by single nucleotide polymorphism (SNP) assay.Serum concentrations of 25(OH)D were highly correlated in MS-concordant pairs (r = 0.83, P < 0.001), but they were not significantly associated with having the disease (P = 0.4) when analyzed by logistic regression. Intraclass correlation for 25(OH)D concentration was significantly greater in MZ pairs (MZ, r: 0.71 > DZ r: 0.32, P = 0.006). Significant associations of 2 CYP27B1 SNP variants and 25(OH)D concentrations were observed.The findings indicate important genetic influences on regulation of seasonal circulating 25(OH)D concentrations in MS twins.

SUBMITTER: Orton SM

PROVIDER: S-EPMC2740974 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis.

Orton Sarah-Michelle SM Morris Andrew P AP Herrera Blanca M BM Ramagopalan Sreeram V SV Lincoln Matthew R MR Chao Michael J MJ Vieth Reinhold R Sadovnick A Dessa AD Ebers George C GC

The American journal of clinical nutrition 20080801 2

<h4>Background</h4>Multiple sclerosis (MS) risk is determined by both genes and environment. One of the most striking features of MS is its geographic distribution, particularly the pattern of high MS frequency in areas with low sunlight exposure, the main inducer of vitamin D synthesis. Recent epidemiologic, experimental, and clinical evidence support an effect for low environmental supplies of vitamin D in mediating an increased susceptibility to MS.<h4>Objectives</h4>We 1) examined the associ ...[more]

PMID: 18689381

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Project description:BackgroundMultiple sclerosis (MS) is a common disease of the central nervous system and a major cause of disability amongst young adults. Genome-wide association studies have identified many novel susceptibility loci including rs2248359. We hypothesized that genotypes of this locus could increase the risk of MS by regulating expression of neighboring gene, CYP24A1 which encodes the enzyme responsible for initiating degradation of 1,25-dihydroxyvitamin D3.MethodsWe investigated this hypothesis using paired gene expression and genotyping data from three independent datasets of neurologically healthy adults of European descent. The UK Brain Expression Consortium (UKBEC) consists of post-mortem samples across 10 brain regions originating from 134 individuals (1231 samples total). The North American Brain Expression Consortium (NABEC) consists of cerebellum and frontal cortex samples from 304 individuals (605 samples total). The brain dataset from Heinzen and colleagues consists of prefrontal cortex samples from 93 individuals. Additionally, we used gene network analysis to analyze UKBEC expression data to understand CYP24A1 function in human brain.FindingsThe risk allele, rs2248359-C, is strongly associated with increased expression of CYP24A1 in frontal cortex (p-value=1.45×10-13), but not white matter. This association was replicated using data from NABEC (p-value=7.2×10-6) and Heinzen and colleagues (p-value=1.2×10-4). Network analysis shows a significant enrichment of terms related to immune response in eight out of the 10 brain regions.InterpretationThe known MS risk allele rs2248359-C increases CYP24A1 expression in human brain providing a genetic link between MS and vitamin D metabolism, and predicting that the physiologically active form of vitamin D3 is protective. Vitamin D3's involvement in MS may relate to its immunomodulatory functions in human brain.FundingMedical Research Council UK; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA.

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Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis.

Publications

Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis.

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