Effect of Variation in Genes of Xenobiotic Responsive Proteins in ALS

描述（由研究者提供）：该项目的目标是识别调节个体对肌萎缩性侧索硬化症（ALS）遗传易感性的环境响应基因的变异。在鉴定家族型ALS的基因（SOD1和ALSIN）和位点（染色体9、15、16、18、2和x）方面取得了相当大的进展，但散发性ALS （SALS）的病因仍然未知。为了解决遗传对SALS的贡献，我们收集了大量的三人组，病例对照和不一致的兄弟姐妹对资源，现在有足够的材料来检验特定的假设。为了实现我们的目标，我们将首先使用功能候选方法筛选两组ALS患者和对照组中410个环境响应基因的遗传变异。检测到的与ALS的关联将在第二组500例病例对照受试者中进行验证。我们使用生物信息学工具从包括NIEHS鉴定的在内的几个数据库中挖掘了一个相当全面的环境响应基因列表。我们将使用高通量基因分型系统筛选这些基因中的变异（SNP），并检查SALS的易感性和表型与这些基因的等位基因关联。初始屏幕将使用250个三人组和500个病例对照对象。有希望的候选人将使用第二组500例病例和对照以及不一致的兄弟姐妹进行验证。此外，我们将研究与SALS相关的基因与基因和基因与环境的相互作用。识别与SALS或SALS亚表型相关的基因变异（例如发病年龄、发病部位、球/脊髓等）将使我们能够测试候选基因所属的整个途径中的基因。因此，该项目将允许使用大量家庭和单例ALS队列资源对环境响应基因进行重点研究，并将为研究ALS发病机制和制定合理治疗方法提供资源。散发性肌萎缩侧索硬化症的病因在很大程度上是未知的，因此不可能进行合理的治疗。对环境毒性的遗传易感性被认为是ALS的基础。我们有一大群ALS患者，兄弟姐妹，父母和对照组。我们将利用这一独特的资源来分析参与环境毒素解毒的基因的DNA变异与ALS的关系，并测试已鉴定的基因与环境暴露的相互作用。本研究将为研究ALS的发病机制，制定合理的治疗方案开辟新的领域。

DESCRIPTION (provided by investigator): The goal of this project is to identify variants in environmentally responsive genes that modulate the genetic susceptibility of individuals to amyotrophic lateral sclerosis (ALS). Considerable progress has been made in identifying genes (SOD1 and ALSIN) and loci (chromosomes 9, 15, 16, 18, 2 and x) in the familial form of ALS but the etiology of sporadic ALS (SALS) remains unknown. To address the genetic contribution to SALS we have collected a large set of trios, case-control and discordant sib-pairs resources and now have sufficient material to test specific hypothesis. To fulfill our goal we will initially use a functional candidate approach to screen genetic variants in 410 environmentally responsive genes in two cohorts of ALS patients and controls. The associations detected with ALS will be verified in a second cohort of 500 case-controls subjects. We have used bioinformatics tools to mine a fairly comprehensive list of environmentally responsive genes from several databases including those identified by the NIEHS. We will screen variants (SNP's) in these genes using a high-throughput genotyping system and examine the SALS susceptibility and phenotype for allelic association to these genes. The initial screen will employ 250 trios and 500 case controls subjects. Promising candidates will be validated using a second set of 500 cases and controls and in discordant sibpairs. Furthermore, we will examine the genes associated with SALS for gene-gene and gene-environment interactions. Identification of gene variants associated with SALS or with the SALS sub-phenotypes (e.g. Age-at-onset, site-of-onset, bulbar/spinal etc.) will allow us to test genes in the entire pathway to which the candidate gene belongs. This project will therefore allow a focused study of environmentally responsive genes using a large resource of family and singleton ALS cohorts and will generate resources to investigate new approaches to ALS pathogenesis and in formulating rational treatment. The causes of sporadic ALS are largely unknown, and rational therapy is therefore not possible. A genetic susceptibility to environmental toxicity is considered to underlie ALS. We have a large cohort of ALS patients, siblings, parents and control subjects. We will use this unique resource to analyze the association of DNA variations in genes involved in detoxification of environmental toxins to ALS, and test the identified genes for their interaction with environmental exposures. This study will open fresh ground to investigative mechanisms of disease in ALS for formulation of rational treatment.