Ramasamy Adaikalavan, Trabzuni Daniah, Forabosco Paola, Smith Colin, Walker Robert, Dillman Allissa, Sveinbjornsdottir Sigurlaug, Hardy John, Weale Michael E, Ryten Mina
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.
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.
Mult Scler Relat Disord. 2014 Mar;3(2):211-219. doi: 10.1016/j.msard.2013.08.009.
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, which encodes the enzyme responsible for initiating degradation of 1,25-dihydroxyvitamin D3.
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 function in human brain.
The risk allele, rs2248359-C, is strongly associated with increased expression of in frontal cortex (-value=1.45×10), but not white matter. This association was replicated using data from NABEC (-value=7.2×10) and Heinzen and colleagues (-value=1.2×10). Network analysis shows a significant enrichment of terms related to immune response in eight out of the 10 brain regions.
The known MS risk allele rs2248359-C increases 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.
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.
多发性硬化症（MS）是中枢神经系统的常见疾病，也是年轻人致残的主要原因。全基因组关联研究已经确定了许多新的易感基因座，包括rs2248359。我们假设该基因座的基因型可能通过调节邻近基因的表达来增加MS风险，该邻近基因编码负责启动1,25 - 二羟基维生素D3降解的酶。
我们使用来自三个独立的欧洲血统神经健康成年人数据集的配对基因表达和基因分型数据来研究这一假设。英国大脑表达联盟（UKBEC）由来自134个人的10个脑区的尸检样本组成（共1231个样本）。北美大脑表达联盟（NABEC）由来自304个人的小脑和额叶皮质样本组成（共605个样本）。Heinzen及其同事的脑数据集由来自93个人的前额叶皮质样本组成。此外，我们使用基因网络分析来分析UKBEC表达数据，以了解其在人脑中的功能。
风险等位基因rs2248359 - C与额叶皮质中该基因表达增加密切相关（P值 = 1.45×10），但与白质无关。使用NABEC的数据（P值 = 7.2×10）和Heinzen及其同事的数据（P值 = 1.2×10）重复了这种关联。网络分析显示，10个脑区中的8个脑区与免疫反应相关的术语显著富集。
已知的MS风险等位基因rs2248359 - C增加了人脑中该基因的表达，为MS与维生素D代谢之间提供了遗传联系，并预测维生素D3的生理活性形式具有保护作用。维生素D3参与MS可能与其在人脑中的免疫调节功能有关。
英国医学研究理事会；沙特阿拉伯法赫德国王专科医院和研究中心；美国国立卫生研究院国立衰老研究所内部研究项目。
