Genome-Wide Association Study in Celiac Disease

描述（由申请人提供）：乳糜泻（谷蛋白敏感性肠病，乳糜泻）是一种发病率和死亡率很高的常见病。它是由对膳食蛋白麸质敏感引起的，导致小肠慢性肠病。乳糜泻现在被认为是一种常见病，据报道，美国的发病率为1:133，与欧洲的估计相似。最近有证据表明这种疾病的发病率正在上升。隐匿性疾病通常表现为极少的典型症状或体征。有症状和无症状乳糜泻的比例估计为1:7。乳糜泻的一些并发症包括淋巴瘤、骨质疏松、贫血、流产、癫痫发作、维生素缺乏和其他自身免疫性疾病的共存。唯一的治疗方法是无麸质饮食，因此轻微的饮食不当可能会导致症状和并发症的复发。确定乳糜泻的潜在遗传原因可能使我们能够确定易感个体，并提出新的方法来预防疾病并在疾病发生后进行治疗。已经进行了几项全基因组连锁研究和一项乳糜泻全基因组关联研究。除了HLA上的共同基因座外，很少有推测的乳糜泻基因座在研究之间被重复，这表明该疾病是异质性和复杂性的。部分遗传易感性可归因于HLA，但病因可能是由于一些罕见的高渗透基因（如连锁分析中所发现的）和更常见的低渗透基因（如关联研究中所发现的）。这项研究的目的是确定增加患乳糜泻风险的新基因位点。我们将利用现有的北美资源，包括两个大型乳糜泻病例和对照（目标1）和一组独立的乳糜泻病例及其家庭（目标3）。我们提出了一个全面的多阶段方法，具体目标如下。在Aim 1中，我们将进行单核苷酸多态性（SNPs）和拷贝数变异（CNVs）的全基因组关联（GWA）研究。GWA将包括1900例疾病病例和3400例匹配对照，使用Illumina Human 610四芯片进行基因分型。将进行统计分析以检验与乳糜泻的关系。在目标2中，我们将对目标1中的GWA数据集和之前的GWA数据集进行组合分析，以确定其他低外显子位点。在Aim 3中，我们将尝试在两个独立的样本集中复制GWA研究的重要发现。在这项研究的结论中，我们期望已经验证了一些来自基因组区域的snp和CNPs，这些snp和CNPs改变了患乳糜泻的风险。这些snp可能在临床和研究水平上都是有用的。这项研究的数据将与科学界共享。

DESCRIPTION (provided by applicant): Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic celiac disease is estimated to be 1:7. Some complications of celiac disease include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. The only treatment is a gluten-free diet, so that recurrence of symptoms and complications may occur after minor dietary indiscretions. Identifying the underlying genetic causes of celiac disease may allow us to identify susceptible individuals, as well as advance new ways to prevent the disease and to treat it once it occurs. Several genome-wide linkage studies and one genome-wide association study of celiac disease have been conducted. Other than the common locus at HLA, few putative celiac disease loci have been replicated between studies, suggesting that the disease is heterogeneous and complex. A portion of the genetic predisposition can be attributed to HLA, but the etiology is likely due to a number of rare, high penetrant genes (as would be identified in linkage analysis) and to more common, low penetrant genes (as would be identified in association studies). The objective of this study is to identify new loci that increase risk to develop celiac disease. We will capitalize on existing North American resources, including two large collections of celiac cases and controls (Aim 1) and an independent set of celiac cases and their families (Aim 3). We propose a comprehensive multi- stage approach, with the following specific aims. In Aim 1, we will conduct a genome-wide association (GWA) study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). The GWA will include1900 disease cases and 3400 matched controls, genotyped using the Illumina Human 610-quad chip. Statistical analyses will be performed to test for associations with celiac disease. In Aim 2, we will conduct a combined analysis of our GWA dataset from Aim 1 and a previous GWA dataset to identify additional low- penetrance loci. In Aim 3, we will attempt to replicate significant findings from the GWA study in two independent sample sets. At the conclusion of this study, we expect to have validated a number of SNPs and CNPs from regions in the genome that alter the risk of developing celiac disease. These SNPs may prove useful at both the clinical and research level. The data from the study will be shared with the scientific community. PUBLIC HEALTH RELEVANCE: This proposal is focused on identifying genes that increase risk to develop celiac disease, a common disease with a population prevalence of almost 1% (1:133) in the United States. Celiac disease is associated with significant morbidity and mortality, and the only therapy is a gluten-free diet, which places a significant dietary burden on the affected individual. The identification of underlying genetic causes for the disease will allow us to identify susceptible individuals, as well as possibly identify better ways to prevent the disease from occurring and to treat it once it occurs.