Long COVID as a putative subtype of chronic fatigue syndrome

长期新冠肺炎是慢性疲劳综合症的一种推定亚型

• 批准号: 10686215
• 负责人: RICHA SAXENA
• 金额: $ 35.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686215
• 关键词: 2019-nCoV; Affect; Autoimmune; Autoimmunity; Biological; COVID-19; COVID-19 pandemic; Cells; Chronic Fatigue Syndrome; Data; Development; Diagnosis; Disease; Disease Pathway; Dysautonomias; Environment; Environmental Risk Factor; Etiology; Fatigue; Future; General Population; Genetic; Genetic Risk; Goals; Grant; HLA Antigens; Headache; Health; Heart Rate; Heritability; Hypersensitivity; Immune; Immune System Diseases; Immune response; Individual; Infection; Infection prevention; Inflammation; Life; Long COVID; Lung; Mendelian randomization; Meta-Analysis; Molecular Mimicry; Onset of illness; Population; Prevalence; Prevention strategy; Public Health; Recovery; Refractory; Relapse; Research; Risk; Risk Factors; SARS-CoV-2 infection; Shapes; Siblings; Symptoms; System; Testing; Time; Tissues; Twin Multiple Birth; Variant; Viral; Work; biobank; cohort; comorbidity; disability; disease diagnosis; disorder risk; flu; genetic risk factor; genetic variant; genome wide association study; individual response; insight; inter-individual variation; pathogen; respiratory; response; risk variant; severe COVID-19; symptomatology; trait; working group

Abstract A hallmark of infection with SARS-CoV-2 is the unpredictable variation in individual health response from those who are asymptomatic to those with life-threatening and refractory respiratory illness, and finally those with long lasting symptoms, here defined as Long COVID. The core symptoms of Long COVID are remarkably like chronic fatigue syndrome (CFS) with multisystem complaints including debilitating fatigue, fluctuating heart rate and headache. In CFS, an infectious trigger has been suspected but not proven and onset often follows flu-like symptoms. As disease mechanisms are not understood, the treatment options are currently symptomatic. Between 0.2-0.4% of the population suffer from CFS. The goal of this proposal is to elucidate the biological mechanisms and risk factors for Long COVID and test the hypothesis that Long COVID is a subtype of chronic fatigue syndrome. To elucidate potential mechanisms, we will use data from three different biobanks, a Long COVID genetics working group we have built and through a CFS consortium. In Aim 1, we will examine genetic risk factors and comorbidities through the Long COVID working group comprising 46 cohorts and over 1.5 million individuals. In addition, we will do a meta-analysis of CFS across three Biobanks (N = 740,000). This analysis will elucidate the connection between CFS and Long COVID and identify risk variants for both diseases. In Aim 2, we will explore contribution from immune molecules that fine tune response to pathogens. The immune defense relies on specific cells to prevent infection or to destroy viral and bacterial agents and the body's own infected cells alike. This aim will examine if the genetic variants that protect from infections, COVID-19, or comorbidities, predispose to Long COVID. We will specifically focus on those regions that have large explanatory power such as the human leukocyte antigen (HLA) in addition to exploring associations genome-wide at established COVID-19 loci. This aim will reveal which immune traits increase risk or protect from Long COVID and CFS, elucidating the type of immune responses responsible for disease development. In Aim 3, we will estimate heritability and shared genetic vs. environmental risk. We will estimate the proportion of environmental and genetic factors behind CFS and Long COVID through analysis of siblings, twins, and the general population in FinnGen and UK Biobank. This aim distinguishes the risk contribution from environmental risk and genetics in the context of a shared environment providing insight into the strength of shared environmental vs. genetic factors that are needed for disease development. The proposed work elucidates risk factors and comorbidities that contribute to CFS and Long COVID including the possibly shared disease etiology, symptomatology, and comorbidity. The project provides biological insights for future disease treatment and facilitates early disease diagnosis.

抽象的 SARS-COV-2感染的标志是个人健康反应的明显变化 对于患有威胁生命和难治性呼吸道疾病的人无症状的人，最后 持久的症状，在这里定义为长期的症状。长互联的核心症状非常像慢性 疲劳综合征（CFS）具有多系统投诉，包括使疲劳，心率波动和 头痛。在CFS中，怀疑具有传染性触发因素，但未证实，并且发作通常遵循流感样 症状。由于疾病机制尚不清楚，因此治疗方案目前是有症状的。 在0.2-0.4％的人口中，患有CFS。该提议的目的是阐明生物学 长期相互兴趣的机制和风险因素，并检验了长卷是慢性亚型的假设 疲劳综合征。为了阐明潜在的机制，我们将使用来自三个不同生物库的数据， 我们已经建立并通过CFS联盟建立了Covid Genetics工作组。在AIM 1中，我们将检查遗传 通过长期共同工作组，包括46个队列和超过150万的风险因素和合并症 个人。此外，我们将对三个生物库（n = 740,000）进行CFS的荟萃分析。这个分析 将阐明CFS与长期相互企业之间的联系，并确定两种疾病的风险变体。目标 2，我们将探索免疫分子的贡献，这些贡献对病原体的微调反应。免疫 防御依赖于特定细胞来防止感染或破坏病毒和细菌剂以及人体自己的 感染细胞。此目的将检查是否可以保护感染，COVID-19或 合并症，易于长期相互兴趣。我们将特别关注那些具有大解释性的地区 除了探索整个基因组的关联外，诸如人类白细胞抗原（HLA）之类的功率 建立的Covid-19基因座。该目标将揭示哪些免疫特征会增加风险或防止长期造成的风险 和CFS，阐明了负责疾病发展的免疫反应的类型。在AIM 3中，我们将 估计遗传力并共享遗传与环境风险。我们将估计环境的比例 通过分析兄弟姐妹，双胞胎和一般人群，CFS背后的遗传因素和长期共同 在芬兰和英国生物库中。这个目标将风险贡献与环境风险和遗传学区分开 共享环境的背景提供了对共享环境与遗传的实力的见解 疾病发展所需的因素。拟议的工作阐明了风险因素和合并症 这有助于CFS和长期共同，包括可能共享的疾病病因，症状和 合并症。该项目为未来的疾病治疗提供了生物学见解，并促进早期疾病 诊断。