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：
10706155
负责人：
Daniel Kastner
金额：
$ 234.17万
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/10706155
关键词：
Adenitis Adopted Adult African American population Alleles American Aphthous Stomatitis Area Arthritis Autoimmune Diseases Autoimmunity Behcet Syndrome Biological Assay Blood Case/Control Studies Cells Cervical Child Childhood Chronic Clinical Clinical Data Clinical Investigator Codon Nucleotides Complex DNA Dependence Disease Drug Tolerance Ear Electronic Publishing Enzymes Eosinophilia European Exanthema Exhibits Extramural Activities Faculty Family Fever Gene Expression Gene Frequency Genes Genetic Genetic study Genomic approach Genomics Genotype Goals HLA-DRB1 Haplotypes Human IL-6 inhibitor Inflammatory Initiator Codon Interleukin-1 Interleukin-6 International Investigation Journals Link Macrophage activation syndrome Manuscripts Medicine Molecular Morbidity - disease rate Mucocutaneous Lymph Node Syndrome Mucous Membrane Multivariate Analysis Mutation Myelogenous National Institute of Allergy and Infectious Disease National Institute of Arthritis, and Musculoskeletal, and Skin Diseases New England New York Organ Pathogenesis Pathogenicity Patients Periodicity Pharmaceutical Preparations Pharyngitis Population Positioning Attribute Predisposition Protein Isoforms Publishing Reaction Recurrence Regulation Reporter Reporting Research Personnel Residual state Rheumatism Rheumatoid Arthritis Role Sampling Scleroderma Sequence Analysis Single Nucleotide Polymorphism Somatic Mutation Susceptibility Gene Symptoms Syndrome Tonsillar Tissue Transfusion Translations Ubiquitin-Activating Enzymes Ulcer Underserved Population Undifferentiated United States National Institutes of Health Universities Vacuole Variant Vascular Diseases anakinra autoinflammation autoinflammatory clinical diagnosis clinical heterogeneity cohort genetic analysis human leukocyte antigen testing in vitro Model inhibitor innovation interest mortality multi-ethnic novel rare variant skin fibrosis survival prediction systemic juvenile idiopathic arthritis tenure track vigilance

项目摘要

VEXAS Syndrome Given the high mortality rate and significant clinical heterogeneity of VEXAS syndrome, we participated in a collaborative effort to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrated that the p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we showed that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we found that a patient, clinically diagnosed with VEXAS syndrome, had two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We concluded that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease pathogenesis. A manuscript reporting these findings was electronically published in Blood during the current reporting period. Systemic Onset Juvenile Idiopathic Arthritis (sJIA; Stills Disease) As part of the INCHARGE Consortium led by former fellow Michael Ombrello, we participated in the analysis of a case/control study of 66 patients with sJIA who exhibited features of drug reaction with eosinophilia and systemic symptoms (DRESS) to inhibitors of interleukin 1 (IL-1) or IL-6, compared with 65 drug-tolerant sJIA controls. Clinical data from all sJIA subjects were retrospectively analyzed and 94/131 were typed for HLA. European sJIA-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium (INCHARGE) pediatric sJIA cases (n=550) and compared for HLA allele frequencies. HLA association was also analyzed using sJIA-DRESS cases (n=64) compared with drug-tolerant sJIA (n=30). Kawasaki disease subjects (n=19) were similarly studied. sJIA-DRESS features included eosinophilia (89%), AST-ALT elevation (75%), and non-evanescent rash (95%). Macrophage activation syndrome during treatment was frequent in sJIA-DRESS (64%) versus drug-tolerant sJIA (3%; p=1.2x10e-14). There was striking enrichment for HLA-DRB1*15 haplotypes in sJIA-DRESS cases versus INCHARGE sJIA controls (p=7.5x10e-13) and versus self-identified, ancestry matched sJIA controls (p=6.3x10e-10). In the Kawasaki disease cohort, DRB*15:01 was present only in those with suspected anakinra reactions. We concluded that DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes, and we suggested consideration of preprescription HLA typing and vigilance for serious reactions. A manuscript reporting these findings was published in the Annals of the Rheumatic Diseases during the current reporting period.

Vexas综合征鉴于Vexas综合征的高死亡率和显着的临床异质性，我们参与了协作努力，以确定Vexas生存的独立预测指标，并了解这些因素的机械基础。我们分析了在P.Met41（P.Met41Leu/thr/val）的UBA1中的83例患者，这是UBA1（UBA1B）细胞质同工型翻译的起始密码子。 P.MET41VAL基因型的患者最有可能患有未分化的炎症综合征。多元分析表明，耳塞炎与生存率增加有关，而输血依赖性和P.MET41VAL变体与生存降低独立相关。使用体外模型和患者衍生的细胞，我们证明了P.MET41VAL变体比P.MET41LEU或P.MET41THR支持的UBA1B翻译少，提供了分子理由，以降低存活率。此外，我们表明，这三种规范的Vexas变体产生的UBA1b比该密码子内的其他六个可能的单核苷酸变体中的任何一个。最后，我们发现一名被临床诊断为VEXAS综合征的患者在同一等位基因上的CIS中发生了两个新的UBA1突变。一个突变（C.121 A> t; p.Met41Leu）在记者测定中导致UBA1B的翻译严重降低，但与第二突变（C.119 g> c; P.Glly40Ala）共表达，从而拯救了UBA1b的水平，向规范性突变的水平拯救了水平。我们得出的结论是，残留的UBA1B翻译的调节是Vexas综合征发病机理的基础，并有助于疾病发病机理。在当前报告期间，一份报告这些发现的手稿以电子方式发表在血液中。系统性发作青少年特发性关节炎（SJIA；静止病）作为由前迈克尔·奥姆布雷洛（Michael Ombrello）领导的INCHARGE联盟的一部分，我们参与了对66例SJIA患者的病例/对照研究的分析，这些患者表现出嗜酸性粒细胞和全身性症状和全身性症状和全身性症状的特征（与65名药物对照组相比，对白介素1（IL-1）或IL-6的抑制剂（IL-1）或IL-6的抑制剂进行了分析。回顾性分析了所有SJIA受试者的临床数据，并为HLA键入94/131。欧洲的SJIA女性病例与国际儿童期遗传学联盟（INCHARGE）小儿SJIA病例（n = 550）相匹配，并比较了HLA等位基因频率。与耐药的SJIA（n = 30）相比，还使用SJIA-DRESS病例（n = 64）分析了HLA关联。类似地研究了川崎疾病受试者（n = 19）。 SJIA-dress特征包括嗜酸性粒细胞增多（89％），AST-ALT升高（75％）和非衰老皮疹（95％）。在治疗过程中，巨噬细胞激活综合征在SJIA-DRESS（64％）与耐药的SJIA（3％; P = 1.2x10e-14）中经常存在。在SJIA-DRESS病例中，HLA-DRB1*15单倍型具有惊人的富集，而SJIA对照组（p = 7.5x10e-13），与自我识别的，祖先相匹配的SJIA对照组（P = 6.3x10e-10）。在川崎疾病队列中，DRB*15：01仅在怀疑是Anakinra反应的患者中存在。我们得出的结论是，在接受IL-1/IL-6抑制剂治疗的患者中发生着着装型反应，并与常见的HLA-DRB1*15单倍型密切相关，我们建议考虑考虑预分量HLA键入和警惕严重反应。在当前报告期间，一份报道这些发现的手稿发表在风湿性疾病的年鉴中。