Genetic Analysis of Complex Inflammatory Disorders

复杂炎症性疾病的遗传分析

• 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
• 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

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著的临床异质性，我们参与了一项合作努力，以确定VEXAS生存的独立预测因素，并了解这些因素的机制基础。我们分析了83例具有UBA 1中p.Met41（p.Met41Leu/Thr/瓦尔）（UBA 1胞质异构体（UBA 1b）翻译的起始密码子）的体细胞致病性变异的患者。具有p.Met41Val基因型的患者最有可能患有未分化的炎症综合征。多变量分析显示，耳炎与生存率增加相关，而输血依赖和p.Met41Val变异与生存率降低独立相关。使用体外模型和患者来源的细胞，我们证明了p.Met41Val变体支持的UBA 1b翻译比p.Met41Leu或p.Met41Thr少，为生存率降低提供了分子基础。此外，我们发现这三个典型的VEXAS变体比该密码子内其他六个可能的单核苷酸变体中的任何一个产生更多的UBA 1b。最后，我们发现一名临床诊断为VEXAS综合征的患者在同一等位基因上有两个UBA 1顺式突变。一个突变（c.121 A>T; p.Met41Leu）在报告基因测定中导致UBA 1b翻译严重减少，但与第二个突变（c.119 G>C; p.Gly40Ala）共表达将UBA 1b水平恢复到典型突变水平。我们的结论是，残余UBA 1b翻译的调节是VEXAS综合征的发病机制的基础，并有助于疾病的发病机制。在本报告期内，报告这些结果的手稿以电子方式发表在《血液》杂志上。 全身性幼年特发性关节炎（sJIA; Stills病） 作为由前研究员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，这些患者对白细胞介素1（IL-1）或IL-6抑制剂表现出嗜酸性粒细胞增多和全身症状（DRESS）的药物反应特征，并与65例耐药sJIA对照进行比较。对所有sJIA患者的临床资料进行回顾性分析，并对94/131例患者进行HLA分型。欧洲sJIA-DRESS病例与国际儿童关节炎遗传学联盟（INCHARGE）儿科sJIA病例（n=550）的祖先匹配，并比较HLA等位基因频率。还使用sJIA-DRESS病例（n=64）与耐药sJIA（n=30）进行了HLA相关性分析。对川崎受试者（n=19）进行了类似的研究。sJIA-DRESS特征包括嗜酸性粒细胞增多（89%）、AST-ALT升高（75%）和非一过性皮疹（95%）。治疗期间巨噬细胞活化综合征在sJIA-DRESS（64%）与耐药sJIA（3%; p=1.2x10e-14）中较为常见。与INCHARGE sJIA对照组（p=7.5x10e-13）和自我鉴定的祖先匹配的sJIA对照组（p=6.3x10e-10）相比，sJIA-DRESS病例中HLA-DRB 1 *15单倍型显著富集。在川崎队列中，DRB*15：01仅存在于疑似阿那白滞素反应的患者中。我们的结论是，DRESS型反应发生在接受IL-1/IL-6抑制剂治疗的患者中，与常见的HLA-DRB 1 *15单倍型密切相关，我们建议考虑处方前HLA分型并警惕严重反应。在本报告所述期间，一份报告这些发现的手稿发表在《风湿病年鉴》上。