Genetic Analysis of Complex Inflammatory Disorders

复杂炎症性疾病的遗传分析

• 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
• 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

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.

类风湿性关节炎 在过去一年中，类风湿性关节炎的遗传学研究继续与合作项目进行。 我们提供了NARAC复制病例和对照的基因型，以确定类风湿性关节炎和乳糜泻之间共有的14个非HLA基因座。 之前对每种疾病的疾病易感性基因座进行的全基因组关联研究发现这两种疾病有6个共同基因座，并表明可能存在其他基因座。 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，合并样本超过38，000个。 在对额外复制样本中的最高相关单核苷酸多态性（SNP）进行基因分型后，（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），另外8个SNP显示P小于5乘以10的负八次方，包括先前在一种疾病中鉴定的扩展到另一种疾病的四个SNP和先前在任一种疾病中未被证实的四个SNP。 14个共有的乳糜泻-RA风险基因座TNFRSF 14、IL 2/IL 21、TNFAIP 3、CTLA 4、REL、TAGAP、SH 2B 3、8q24.2、TRAF 1、STAT 4、DDX 6、CD 247、UBE 2L 3和UBASH 3A指向T细胞受体信号传导作为RA和乳糜泻的疾病发病机制的关键共有途径。 我们还贡献了NARAC收集的基因型数据，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。 这对于充分利用来自样本集合（例如NARAC集合）的最大信息尤其重要，所述样本集合是针对同胞对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全面的研究与PFAPA患者期间和之间的发热事件。虽然我们已经观察到PFAPA患者经常有亲属在儿童时期经历过一种或多种PFAPA特征，但没有孟德尔遗传模式，发病机制也不清楚。使用系统生物学方法，我们分析了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热（HPF），健康儿童和儿科HPF患者。基因表达谱清楚地区分PFAPA患者的症状期和无症状期以及HPFs儿童的症状期。在有症状的PFAPA发作期间，补体（C1 QB、C2、SERPING 1）、白细胞介素（IL）-1相关（IL 1B、IL 1 RN、CASP 1、IL 18 RAP）和干扰素诱导（AIM 2、IP 10/CXCL 10）基因显著过表达，而T细胞相关转录本（CD 3、CD 8B）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/CXCL 10、IL-10/CXCL 9）的血清水平显著升高。在PFAPA发作期间还观察到相对淋巴细胞减少。活化CD 4 +/CD 25 + T淋巴细胞计数与IP-10/CXCL 10血清浓度呈负相关，与IL-1受体拮抗剂血清浓度呈正相关。基于PFAPA发作中IL-1 β激活的证据，我们在发作开始时用重组IL-1受体拮抗剂治疗了5例PFAPA患者，所有5例患者均表现出迅速的临床和IP-10/CXCL 10应答。这些数据表明，在有症状的PFAPA发作期间，补体、IL-1 β和IL-18的宿主源性活化，诱导Th 1趋化因子，随后在外周组织中保留活化的T细胞。因此，IL-1抑制可能有利于PFAPA发作的治疗，IP-10/CXCL 10可作为潜在的新生物标志物。今年早些时候，这项工作发表在PNAS上。