Genetic Analysis of Complex Inflammatory Disorders

复杂炎症性疾病的遗传分析

基本信息

批准号：
8350022
负责人：
Daniel Kastner
金额：
$ 46.04万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8350022
关键词：
American Aphthous Stomatitis Area Biological Markers Blood specimen CASP1 gene CD3 Antigens CD8B1 gene CTLA4 gene CXCL10 gene CXCL9 gene CXCR3 gene Celiac Disease Cervical Child Childhood Clinical Collection Complement Complement Activation Complex Data Data Set Disease Disease Pathway Disease susceptibility Effectiveness Family Relationship Fever Flare Gene Expression Profiling Genes Genetic Genetic screening method Genotype Goals Granulocyte Colony-Stimulating Factor Human IL2 gene IL2RA gene Individual Inflammatory Inheritance Patterns Inherited Interferons Interleukin-1 Interleukin-1 beta Interleukin-18 Interleukin-6 Investigation Lymphatic Diseases Lymphocyte Count Lymphopenia Meta-Analysis Methods Pathogenesis Patients Peripheral Pharyngitis Predisposition Proteins Publishing Receptor Signaling Recombinant Interleukin-1 Recurrence Relative (related person)Rheumatoid Arthritis Risk STAT4 gene Sampling Serum Single Nucleotide Polymorphism Syndrome Systems Biology T-Cell Receptor T-Lymphocyte TNF receptor-associated factor 1 Time Tissues Transcript Variant Work anakinra base case control chemokine cytokine experience genetic analysis genome wide association study herpesvirus entry mediator interleukin-21 overexpression response sample collection

项目摘要

Rheumatoid arthritis Genetic studies in rheumatoid arthritis continued with collaborative projects over the past year. We contributed genotypes of NARAC replication cases and controls to a study that identified fourteen non-HLA loci in common between rheumatoid arthritis and celiac disease. Previous genome-wide association studies for disease susceptibility loci for each disease found 6 loci in common for the two diseases and suggested that additional loci likely exist. We therefore performed a meta-analysis of two existing large genome-wide association datasets (RA and celiac disease) with over 38,000 combined samples. After genotyping the top associated single nucleotide polymorphisms (SNPs) in additional replication samples (2,169 celiac disease cases and 2,255 controls, and 2,845 RA cases and 4,944 controls), eight additional SNPs demonstrated P less than 5 times 10 to the negative eighth, including four SNPs previously identified in one disease that were extended to the other disease and four SNPs that have not been previously confirmed in either disease. The fourteen shared celiac disease-RA risk loci, TNFRSF14, IL2/IL21, TNFAIP3, CTLA4, REL, TAGAP, SH2B3, 8q24.2, TRAF1, STAT4, DDX6, CD247, UBE2L3, and UBASH3A, point to T-cell receptor signaling as a key shared pathway of disease pathogenesis for RA and celiac disease. We also contributed genotype data for the NARAC collection that were used to develop and demonstrate the effectiveness of a simple new method to include related individuals in case control association studies. This is particularly important to leverage the maximum information from collections of samples such as the NARAC collection, which were collected targeting sib-pair or other family relationship samples. PFAPA During the last year we have completed a comprehensive study of patients with PFAPA during and between febrile episodes. Although we have observed that PFAPA patients frequently have relatives who experienced one or more features of PFAPA in childhood, there is not a Mendelian pattern of inheritance, and the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients after genetic testing to exclude other known hereditary periodic fevers (HPFs), from healthy children, and from pediatric HPF patients. Gene expression profiling clearly distinguished symptomatic and asymptomatic periods in PFAPA patients and symptomatic periods in children with HPFs. During symptomatic PFAPA episodes, complement (C1QB, C2, SERPING1), interleukin (IL)-1-related (IL1B, IL1RN, CASP1, IL18RAP), and interferon-induced (AIM2, IP10/CXCL10) genes were significantly overexpressed, while T cell-associated transcripts (CD3, CD8B) were downregulated. At the protein level, symptomatic PFAPA episodes manifested significantly increased serum levels of granulocyte colony-stimulating factor, proinflammatory cytokines (IL-18, IL-6), and chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9). A relative lymphopenia was also noted during PFAPA attacks. Activated CD4 positive/CD25 positive T lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, but positively with those of IL-1 receptor antagonist. Based on the evidence for IL-1beta activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist at the beginning of a flare and all five demonstrated a prompt clinical and IP-10/CXCL10 response. These data suggest a host-derived activation of complement, IL-1beta, and IL-18 during symptomatic PFAPA episodes, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for the treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential new biomarker. Earlier this year this work was published in the PNAS.

类风湿关节炎在过去的一年里，类风湿关节炎的遗传学研究继续通过合作项目进行。我们为一项研究贡献了 NARAC 复制病例和对照的基因型，该研究确定了类风湿性关节炎和乳糜泻之间共有的 14 个非 HLA 位点。先前针对每种疾病的疾病易感性位点的全基因组关联研究发现这两种疾病有 6 个共同位点，并表明可能存在其他位点。因此，我们对两个现有的大型全基因组关联数据集（RA 和乳糜泻）进行了荟萃分析，包含超过 38,000 个组合样本。在对其他复制样本（2,169 例乳糜泻病例和 2,255 例对照，以及 2,845 例 RA 病例和 4,944 例对照）中最相关的单核苷酸多态性 (SNP) 进行基因分型后，另外 8 个 SNP 证明 P 小于 5 乘以 10 的负八分之一，其中包括 4 个先前在一种疾病中发现的 SNP 已扩展到另一种疾病，还有 4 个 SNP 先前未在任何一种疾病中得到证实。 14 个共有的乳糜泻-RA 风险位点：TNFRSF14、IL2/IL21、TNFAIP3、CTLA4、REL、TAGAP、SH2B3、8q24.2、TRAF1、STAT4、DDX6、CD247、UBE2L3 和 UBASH3A，指向 T 细胞受体信号传导作为 RA 和乳糜泻疾病发病机制的关键共享途径。我们还为 NARAC 收集提供了基因型数据，这些数据用于开发和证明一种简单的新方法的有效性，该方法将相关个体纳入病例对照关联研究。这对于充分利用样本集合（例如 NARAC 集合）中的最大信息尤为重要，这些样本是针对同胞对或其他家庭关系样本收集的。 PFAPA 去年，我们完成了一项针对 PFAPA 患者发热期间和发热期间的综合研究。尽管我们观察到 PFAPA 患者经常有亲属在童年经历过 PFAPA 的一种或多种特征，但不存在孟德尔遗传模式，发病机制尚不清楚。我们使用系统生物学方法分析了 PFAPA 患者在基因检测后的血液样本，以排除其他已知的遗传性周期性发烧 (HPF)、健康儿童和儿科 HPF 患者。基因表达谱清楚地区分了 PFAPA 患者的有症状期和无症状期以及 HPF 儿童的有症状期。在有症状的 PFAPA 发作期间，补体（C1QB、C2、SERPING1）、白细胞介素 (IL)-1 相关（IL1B、IL1RN、CASP1、IL18RAP）和干扰素诱导的（AIM2、IP10/CXCL10）基因显着过表达，而 T细胞相关转录本（CD3、CD8B）下调。在蛋白质水平上，有症状的 PFAPA 发作表现为粒细胞集落刺激因子、促炎细胞因子（IL-18、IL-6）和活化 T 淋巴细胞趋化因子（IP-10/CXCL10、MIG/CXCL9）的血清水平显着升高。在 PFAPA 发作期间还注意到相对的淋巴细胞减少。活化的CD4阳性/CD25阳性T淋巴细胞计数与IP-10/CXCL10的血清浓度呈负相关，但与IL-1受体拮抗剂的血清浓度呈正相关。根据 PFAPA 发作中 IL-1β 激活的证据，我们在发作开始时使用重组 IL-1 受体拮抗剂治疗了 5 名 PFAPA 患者，所有 5 名患者均表现出迅速的临床和 IP-10/CXCL10 反应。这些数据表明，在有症状的 PFAPA 发作期间，宿主源性激活补体、IL-1β 和 IL-18，并诱导 Th1 趋化因子，随后激活的 T 细胞保留在外周组织中。因此，IL-1 抑制可能有利于 PFAPA 攻击的治疗，而 IP-10/CXCL10 可以作为潜在的新生物标志物。今年早些时候，这项工作发表在《美国国家科学院院刊》上。