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中，类风湿关节炎的遗传研究继续进行协作项目。我们为NARAC复制病例和对照组的基因型贡献了一项研究，该研究确定了14个非HLA基因座，在类风湿关节炎和乳糜泻之间共有。对每种疾病的疾病敏感性基因座的先前全基因组关联研究发现了这两种疾病的共同点有6个基因座，并表明可能存在额外的基因座。因此，我们对两个现有的全基因组关联数据集（RA和腹腔疾病）进行了荟萃分析，并进行了38,000多个组合样品。在其他复制样本（2,169例乳糜泻病例和2,255例对照，2,845例RA病例和4,944例对照中）中，在基因分型之后，在其他复制样本中具有最高的单核苷酸多态性（SNP）之后疾病。 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. 我们还为NARAC收集贡献了基因型数据，这些数据用于开发和证明一种简单的新方法的有效性，将相关个体纳入案例控制关联研究中。这对于利用诸如NARAC集合等样品的收集收集的最大信息尤为重要，这些信息是针对SIB-PAIR或其他家庭关系样本收集的。 PFAPA 在过去的一年中，我们已经完成了一项对PFAPA患者在高热发作之间的全面研究。尽管我们观察到PFAPA患者经常有亲戚在童年时期经历过一种或多种PFAPA的特征，但没有孟德尔的遗传模式，并且发病机理尚不清楚。使用系统生物学方法，我们在基因检测后分析了PFAPA患者的血液样本，以排除其他已知的遗传周期性发烧（HPF），健康的儿童和小儿HPF患者。 PFAPA患者的基因表达谱图明显区分了症状和无症状时期和HPF儿童的症状时期。在有症状的PFAPA发作期间，补体（C1QB，C2，Serping1），白介素（IL）-1相关（IL1B，IL1B，IL1RN，CASP1，IL18RAP）和干扰素诱导（AIM2，IP10/CXCL10）基因douptermed down down douptermed down cad-down downrem dows cad systrem cd8，cd 3 sysc. cd3 systrect cd 3。在蛋白质水平上，有症状的PFAPA发作表现出明显升高的粒细胞刺激因子的血清水平，促炎细胞因子（IL-18，IL-6）和激活的T淋巴细胞的趋化因子（IL-18，IL-6）（IP-10/CXCL10，MIG/CXCL9）。在PFAPA攻击期间，还发现了相对淋巴细胞减少症。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受体拮抗剂的阳性计数相阳性。基于PFAPA耀斑中IL-1BETA激活的证据，我们在耀斑开始时用重组IL-1受体拮抗剂治疗了5例PFAPA患者，所有五个均显示出迅速的临床和IP-10/CXCL10反应。这些数据表明，在有症状的PFAPA发作过程中，宿主衍生的补体，IL-1Beta和IL-18的激活，并诱导Th1-脱脂因子并随后在外周组织中保留活化的T细胞。因此，IL-1抑制作用可能对治疗PFAPA攻击有益，而IP-10/CXCL10则是一种潜在的新生物标志物。今年早些时候，这项工作发表在PNA中。