Genome-Wide Association Study in Celiac Disease

描述（由申请方提供）：乳糜泻（谷蛋白敏感性肠病，乳糜泻）是一种常见疾病，发病率和死亡率较高。它是由对膳食蛋白质面筋的敏感性引起的，导致小肠的慢性肠病。乳糜泻现在被认为是一种常见疾病，据报道，在美国，该病的发病率为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。隐匿性疾病常伴有最小的典型症状或体征。有症状与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、骨质疏松症、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同发生。唯一的治疗方法是无麸质饮食，因此在轻微的饮食不当后可能会出现症状复发和并发症。确定乳糜泻的潜在遗传原因可能使我们能够识别易感个体，并提出新的方法来预防疾病并在发生时进行治疗。已经进行了几项全基因组连锁研究和一项乳糜泻的全基因组关联研究。除了在HLA的共同位点，很少有假定的乳糜泻位点已被复制的研究之间，这表明该疾病是异质性和复杂性。一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外显基因（如在连锁分析中所确定的）和更常见的低外显基因（如在关联研究中所确定的）。这项研究的目的是确定新的基因座，增加风险发展为乳糜泻。我们将利用现有的北美资源，包括两个大的收集腹腔病例和控制（目标1）和一个独立的腹腔病例和他们的家庭（目标3）。我们提出一个多阶段的综合办法，具体目标如下。在目标1中，我们将进行单核苷酸多态性（SNP）和拷贝数变异（CNVs）的全基因组关联（GWA）研究。GWA将包括1900个疾病病例和3400个匹配的对照，使用Illumina Human 610-quad芯片进行基因分型。将进行统计分析，以检验与乳糜泻的相关性。在目标2中，我们将对来自目标1的GWA数据集和先前的GWA数据集进行组合分析，以鉴定额外的低等位基因座。在目标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来自基因组中改变乳糜泻风险的区域的一些SNP和CNP。这些SNP可能在临床和研究水平上都很有用。研究数据将与科学界共享。 公共卫生相关性：这项提案的重点是确定增加患乳糜泻风险的基因，乳糜泻是一种常见疾病，在美国的人口患病率几乎为1%（1：133）。乳糜泻与显著的发病率和死亡率相关，唯一的治疗方法是无麸质饮食，这给受影响的个体带来了显著的饮食负担。确定这种疾病的潜在遗传原因将使我们能够确定易感个体，并可能确定更好的方法来预防疾病的发生和一旦发生就进行治疗。

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.