Celiac Disease: From Genetic Risk to Disease Development

描述（由申请人提供）：乳糜泻（乳糜泻，麸质敏感性肠病，乳糜泻）是一种常见疾病，如果不治疗，发病率会很高。它是由对小麦、黑麦和大麦中存在的膳食蛋白麸质敏感引起的。谷蛋白敏感性肠病是指小肠的组织学异常。它现在被认为是一种常见病，据报道，美国的发病率为1:150，与欧洲的估计相似。在高度特异和敏感的抗体测试出现之前，乳糜泻的诊断不足。最近，有人提出，除了更好的诊断，乳糜泻的发病率也在增加。隐匿性疾病通常表现为极少的典型症状或体征。有症状的乳糜泻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、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。没有可用的药物治疗。虽然用无麸质饮食治疗会改善症状，但轻微的饮食不当可能会导致症状复发和并发症。本提案将重点关注几个尚未解决的公共卫生问题。乳糜泻高风险人群是否值得继续筛查？是否存在诱发易感人群发病的应激事件？通过筛查早期发现乳糜泻是否能降低与乳糜泻相关的其他自身免疫性疾病发生的风险？乳糜泻患者如果不坚持无谷蛋白饮食是否更容易出现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个家庭研究的个体，一个在加州大学欧文分校，一个在梅奥诊所，我们系统地进行了血清学和HLA检测，并收集了乳糜泻家庭成员的症状数据。目的1是调查5年或5年以上既往检测为阴性的乳糜泻患者一级亲属的乳糜泻发展情况。我们将对乳糜泻进行血清学检测，并让受试者完成一份随访问卷，包括一般健康状况、乳糜泻症状、相关疾病、饮食和可能引发乳糜泻的主要生活事件等数据项。目的二是调查作为乳糜泻患者甲状腺炎、I型糖尿病、恶性贫血和类风湿性关节炎生物标志物的自身抗体的流行情况。我们将从至少5年前诊断的乳糜泻病例中获得新的血清和随访问卷。本研究将解决两个关键的CD公共卫生管理问题：1)是否有必要对先前检测阴性的高危人群进行重新检测；2)是否可以通过无谷蛋白饮食来减轻乳糜泻与其他自身免疫性疾病的关联。这些结果将提供信息，以促进转化为临床管理的疾病及其合并症的条件。该提案的重点是乳糜泻的公共卫生影响，乳糜泻是一种常见于美国的疾病，人口患病率为1:150。首先，我们将确定对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预防发展、延迟发病或减轻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.