Genome and Phenome to Define Disease Risk with Antinuclear Antibodies

使用抗核抗体定义疾病风险的基因组和表型组

• 批准号: 10405061
• 负责人: Vivian K Kawai
• 金额: $ 55.31万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-14 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405061
• 关键词: Academic Medical Centers; Address; Affect; Animals; Antibodies; Antinuclear Antibodies; Arthralgia; Autoantigens; Autoimmune Diseases; Bioinformatics; Cardiovascular system; Caring; Catalogs; Clinical; Clinical Data; Computerized Medical Record; Data; Detection; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early treatment; Electronic Health Record; Future; General Population; Genetic; Genetic Determinism; Genetic Risk; Genetic Techniques; Genome; Genotype; Healthcare; Human; Immune; Individual; Infection; Inflammation; Knowledge; Lead; Link; Lupus; Medical Genetics; Mendelian disorder; Modeling; Morbidity - disease rate; Musculoskeletal; Myalgia; Onset of illness; Pathogenicity; Patients; Persons; Phenotype; Prevalence; Reporting; Research Personnel; Risk; Short Interspersed Nucleotide Elements; Symptoms; Systemic Lupus Erythematosus; Techniques; Testing; Time; Uncertainty; Validation; accurate diagnosis; adverse outcome; base; biobank; cancer risk; clinical phenotype; clinical risk; clinically significant; diagnostic strategy; disorder risk; genetic approach; genetic architecture; genetic information; genome wide association study; high risk; improved; mortality; novel; phenome; predictive modeling; prevent; renal damage; risk prediction; side effect; tool; virtual

PROJECT SUMMARY Antinuclear antibodies (ANA) are antibodies that react against self-antigens and are commonly used to help diagnose systemic lupus erythematosus (SLE). Because the test is positive (ANA+) in almost every patient with SLE— even years before the disease onset—a positive ANA test is considered virtually a requisite for the diagnosis of SLE. However, the test is also positive in a large proportion of the general population (~20%). Although very few of these ANA+ individuals will develop an autoimmune disease in the future, the clinical impact of a positive ANA in people without autoimmune disease is unknown. A second problem is that the common occurrence of ANA+ in people without autoimmune disease can lead to the problem of an incorrect diagnosis of SLE, particularly if an ANA+ person also has joint or muscle pain. To more accurately diagnose SLE and prevent false diagnoses, we need to address two major knowledge gaps: 1) we need to understand the importance of a positive ANA test in people without an autoimmune disease; and 2) we need to be able to predict which people with a positive ANA test have or will develop SLE. In this study we will evaluate the overarching hypothesis that clinical and genetic information can: 1) define the clinical consequences of positive ANA in people without autoimmune diseases, and 2) improve risk prediction to differentiate people with increased risk of SLE. Thus, we proposed three Specific Aims: 1) test the hypothesis that a positive ANA in people without autoimmune disease is associated with clinical phenotypes (using a clinical and a genetic approach); 2) test the hypothesis that a clinical prediction model will accurately discriminate patients with early SLE or who are at risk for SLE from among those with positive ANA without an autoimmune disease; and 3) test the hypothesis that the combination of genetic and clinical information will accurately discriminate patients at risk for SLE. To address these aims, we will use the Vanderbilt University Medical Center Biobank (BioVU) and de-identified electronic health records (EHR) to create genetic and clinical risk scores using state-of-the-art genetic techniques and data-driven prediction tools. The results of these studies could: a) define whether people with a positive ANA and no autoimmune disease have an altered risk of illnesses that could be used to guide health-care decisions; and b) transform the care of SLE by improving the accuracy of early-stage SLE diagnosis and identify patients at highest future risk. These findings will help clinicians start treatment earlier to control inflammation and prevent damage and will decrease the rates of misdiagnosis, thereby protecting patients from unnecessary therapies and their side effects.

项目摘要 抗核抗体（ANA）是对自我抗原反应的抗体，通常用于帮助 诊断全身性红斑狼疮（SLE）。因为几乎每个患者的测试是正（ANA+） 在SLE（即使在疾病发作之前），ANA阳性测试实际上是必需的 SLE诊断。但是，该测试在很大一部分人群中也是阳性的（约20％）。 尽管这些ANA+个体中很少会在将来患上自身免疫性疾病，但临床 阳性ANA对没有自身免疫性疾病的人的影响尚不清楚。第二个问题是 没有自身免疫性疾病的人的ANA+常见发生可能导致不正确的问题 诊断SLE，特别是如果ANA+人也患有关节疼痛或肌肉疼痛。更准确地诊断 SLE并防止虚假诊断，我们需要解决两个主要的知识差距：1）我们需要了解 在没有自身免疫性疾病的人中进行阳性ANA测试的重要性； 2）我们需要能够 预测哪些阳性ANA测试的人已经或将会发展为SLE。 在这项研究中，我们将评估临床和遗传信息可以：1）的总体假设 定义没有自身免疫性疾病的人的阳性ANA的临床后果，2） 提高风险预测，以使SLE风险增加的人区分人。那我们提出了三个 具体目的：1）检验以下假设：没有自身免疫性疾病的人的正ANA 使用临床表型（使用临床和遗传方法）； 2）检验临床的假设 预测模型将准确区分早期SLE的患者，或者在 那些没有自身免疫性疾病的ANA阳性的人； 3）检验的假设是 遗传和临床信息将准确区分有SLE风险的患者。为了解决这些目标，我们 将使用范德比尔特大学医学中心生物银行（BIOVU）和去识别的电子健康记录 （EHR）使用最先进的遗传技术和数据驱动 预测工具。 这些研究的结果可能：a）定义ANA阳性和无自身免疫性疾病的人是否定义 有可能用来指导医疗决定的疾病风险的改变； b）改变护理 通过提高早期SLE诊断的准确性并确定未来风险最高的患者，SLE。这些 调查结果将帮助临床医生更早开始治疗以控制注射和预防损害，并将 降低诊断率的率，从而保护患者免受不必要的疗法及其一侧 效果。