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Mult Scler Relat Disord. 2014 Mar;3(2):211-219.

Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis.

Author information

1
King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London SE1 9RT, UK ; Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, England, UK.
2
Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, England, UK ; Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.
3
Istituto di Genetica delle Popolazioni - CNR, Sassari, Italy.
4
Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh EH8 9AG, Scotland, UK.
5
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
6
Department of Neurology, MEHT, Broomfield Hospital, Court Road, CM1 7ET Essex, UK ; Department of Neurology, Queen Mary College, University of London, UK.
7
Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, England, UK.
8
King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London SE1 9RT, UK.

Abstract

BACKGROUND:

Multiple 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.

METHODS:

We 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.

FINDINGS:

The 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.

INTERPRETATION:

The 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.

FUNDING:

Medical 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.

KEYWORDS:

CYP24A1; Expression quantitative trait loci; Genetics; Genome-wide association studies; Multiple sclerosis; Vitamin D

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