Celiac Disease: From Genetic Risk to Disease Development

描述（由申请方提供）：乳糜泻（CD，谷蛋白敏感性肠病，乳糜泻）是一种常见疾病，如果不治疗，发病率很高。它是由对小麦、黑麦和大麦中存在的膳食蛋白质面筋敏感引起的。术语谷蛋白敏感性肠病是指小肠的组织学异常。现在它被认为是一种常见疾病，有报道称，美国的疾病频率为1：150，与欧洲的估计相似。在开发高度特异性和敏感性的抗体测试之前，CD诊断不足。最近，有人提出，除了更好的诊断，CD的发病率也在增加。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CD的比例估计为1：7。CD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。无可用的药物治疗。虽然用无麸质饮食治疗会改善症状，但在轻微的饮食不当后可能会出现症状复发和并发症。有几个未解决的公共卫生问题将在本提案中集中讨论。CD高风险个体是否需要继续筛查？是否存在引发易感个体疾病的假定压力事件？通过筛查早期发现CD是否可降低已知与CD相关的其他自身免疫性疾病的发生风险？如果不坚持无麸质饮食，被诊断为CD的个体是否有更高的风险患上其他自身免疫性疾病和其他症状？为了调查这些问题，我们将重新联系之前参加过两项家族研究的个体，一项在加州欧文大学，另一项在马约诊所，在这两项研究中，我们系统地进行了血清学和HLA检测，并收集了来自CD家族的家族成员的症状数据。目的1是调查CD病例的一级亲属中CD的发展，这些病例在五年或五年以上以前曾检测为阴性。我们将对CD进行血清学检测，并让受试者完成随访问卷，包括关于一般健康状况、CD症状、相关疾病、饮食和主要生活事件（作为CD的潜在触发因素）的数据项。目的2是调查自身抗体的患病率，作为甲状腺炎，I型糖尿病，恶性贫血，类风湿性关节炎的CD病例的生物标志物。我们将从至少五年前确诊的CD病例中获得新的血清和随访问卷。这项研究将解决CD中的两个关键公共卫生管理问题：1）对于那些先前检测阴性的高风险人群是否有必要重新检测; 2）CD与其他自身免疫性疾病的关联是否可以通过遵循无麸质饮食来减轻。这些结果将提供信息，以促进转化为临床管理的疾病及其共病conditions.This建议的重点是公共卫生的影响，腹腔疾病，一种常见的疾病，人口患病率为1：150在美国。首先，我们将确定是否一个单一的测试在疾病的高风险的个人腹腔疾病是足够的，或者是否重复测试是必要的。其次，我们将确定乳糜泻对其他自身免疫性疾病发展的影响，以及坚持无麸质饮食是否可以预防发展，延迟发作或减少其他自身免疫性疾病的症状。

DESCRIPTION (provided by applicant): Celiac disease (CD, gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity if untreated. It is caused by sensitivity to the dietary protein gluten, which is present in wheat, rye and barley. The term gluten-sensitive enteropathy refers to the histologic abnormality of the small intestine. It is now recognized to be a common disease, with reports that the disease frequency is 1:150 in the US, similar to European estimates. Before the development of highly specific and sensitive antibody tests, CD was under-diagnosed. Recently, it has been proposed that in addition to better diagnosis, CD is also increasing in incidence. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic CD is estimated to be 1:7. Some complications of CD include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. No pharmacological treatment is available. Although treatment with a gluten-free diet will improve symptoms, recurrence of symptoms and complications may occur after minor dietary indiscretions. There are several unaddressed public health concerns that will be focused on in this proposal. Do individuals at high risk of CD warrant continued screening and are there putative stress events that trigger the disease in susceptible individuals? Does the early detection of CD by screening reduce the risk of development of additional autoimmune disorders that are known to be associated with CD? Are individuals diagnosed with CD at higher risk of developing other autoimmune diseases and additional symptoms if they do not adhere to a gluten-free diet? To investigate these questions, we will recontact individuals previously enrolled in two family studies, one at the University of California Irvine and one at Mayo Clinic, in which we had systematically performed serologic and HLA testing and collected symptom data for family members from CD families. Aim 1 is to investigate the development of CD in first-degree relatives of CD cases who previously tested negative five or more years ago. We will perform serologic testing for CD and have the subjects complete a follow-up questionnaire including data items on general health, CD symptoms, associated-diseases, diet, and major life events as potential triggers for CD. Aim 2 is to investigate the prevalence of auto-antibodies that serve as biomarkers for thyroiditis, type I diabetes, pernicious anemia, and rheumatoid arthritis in CD cases. We will obtain new sera and follow-up questionnaires from CD cases diagnosed at least five years ago. This study will address two critical public health management issues in CD: 1) whether retesting is necessary for those at high-risk who have previously tested negative; and 2) whether the association of CD with other auto-immune diseases can be mitigated by following a gluten-free diet. These results will provide information to facilitate translation into clinical management of the disease and its comorbid conditions.This proposal is focused on the public health implications of celiac disease, a common disease with a population prevalence of 1:150 in the US. First, we will determine whether a single test for celiac disease in individuals at high risk of disease is adequate or whether repeat testing is necessary. Second, we will determine the impact of celiac disease on the development of other autoimmune diseases, and whether adherence to a gluten-free diet can prevent development, delay onset, or reduce symptoms of other auto-immune diseases.