Celiac Disease: From Genetic Risk to Disease Development

描述(申请人提供)：乳糜泻(CD，面筋过敏性肠病，乳糜泻)是一种常见疾病，如果不治疗，发病率很高。它是由小麦、黑麦和大麦中存在的膳食蛋白面筋敏感引起的。谷蛋白敏感型肠病是指小肠的组织学异常。它现在被认为是一种常见疾病，有报道称，美国的患病频率为1：150，与欧洲的估计相似。在开发高度特异和敏感的抗体测试之前，CD被低估了。最近，有人提出，除了诊断更好之外，CD的发病率也在增加。隐匿性疾病通常表现为轻微的典型症状或体征。有症状和无症状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、维生素缺乏以及其他自身免疫性疾病的并存。目前还没有可用的药物治疗。虽然无麸质饮食治疗会改善症状，但在饮食上稍有失慎后，症状和并发症可能会复发。有几个未解决的公共卫生问题将在这项提案中得到关注。CD高危人群是否需要继续筛查？易感人群中是否存在引发疾病的应激事件？通过筛查及早发现CD是否可以降低患其他已知与CD相关的自身免疫性疾病的风险？如果不坚持无麸质饮食，被诊断为CD的人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，我们将重新联系以前参加过两项家庭研究的个人，一项在加州大学欧文分校，另一项在梅奥诊所，在这两项研究中，我们系统地进行了血清学和人类白细胞抗原测试，并收集了CD家庭成员的症状数据。目的1是研究5年前或更多年前试验为阴性的CD病例的一级亲属中CD的发生情况。我们将对CD进行血清学测试，并让受试者完成一份跟踪调查问卷，其中包括一般健康、CD症状、相关疾病、饮食和作为CD潜在触发因素的主要生活事件的数据项。目的2是调查自身抗体在CD病例中作为甲状腺炎、I型糖尿病、恶性贫血和类风湿性关节炎生物标志物的流行率。我们将从至少五年前诊断的CD病例中获得新的血清和后续调查问卷。这项研究将解决CD中的两个关键公共卫生管理问题：1)以前检测为阴性的高危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缓解。这些结果将为将该疾病及其并存情况转化为临床管理提供信息。这项建议侧重于乳糜泻对公众健康的影响，乳糜泻是一种常见疾病，在美国的人口患病率为1：150。首先，我们将确定对疾病高危人群进行一次乳糜泻检测是否足够，或者是否需要重复检测。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防止其他自身免疫性疾病的发生、延迟发病或减轻症状。

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.