van Es Michael A, Van Vught Paul W, Blauw Hylke M, Franke Lude, Saris Christiaan G, Andersen Peter M, Van Den Bosch Ludo, de Jong Sonja W, van 't Slot Ruben, Birve Anna, Lemmens Robin, de Jong Vianney, Baas Frank, Schelhaas Helenius J, Sleegers Kristel, Van Broeckhoven Christine, Wokke John H J, Wijmenga Cisca, Robberecht Wim, Veldink Jan H, Ophoff Roel A, van den Berg Leonard H
Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
Lancet Neurol. 2007 Oct;6(10):869-77. doi: 10.1016/S1474-4422(07)70222-3.
Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS.
We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study.
A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016).
Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
肌萎缩侧索硬化症（ALS）是一种毁灭性疾病，其特征是大脑和脊髓中的运动神经元进行性退化。ALS被认为是多因素导致的，既有环境因素也有遗传因素。我们的目的是识别易患散发性ALS的基因变异。
我们使用Illumina 300K单核苷酸多态性（SNP）芯片，对来自荷兰的461例ALS患者和450例对照进行了三阶段全基因组关联研究。在来自荷兰、比利时和瑞典的独立样本系列中，对另外876例患者和906例对照分析了与ALS关联最密切的SNP。我们还利用散发性ALS患者全血以及全基因组关联研究中纳入的对照个体的表达数据，研究了相关基因可能的病理功能。
肌醇1,4,5-三磷酸受体2基因（ITPR2）中的一个基因变异与ALS相关（经Bonferroni校正后p = 0.012）。对所有样本（1337例患者和1356例对照）的联合分析证实了这种关联（p = 3.28×10⁻⁶，比值比1.58，95%置信区间1.30 - 1.91）。126例ALS患者外周血中的ITPR2表达高于126例健康对照（p = 0.00016）。
ITPR2基因变异是ALS的一个易感因素。ITPR2是ALS的一个强有力的候选易感基因，因为它参与谷氨酸介导的神经传递，是细胞内钙浓度的主要调节因子之一，并且在细胞凋亡中起重要作用。
