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.

韦克斯综合症鉴于 VEXAS 综合征的高死亡率和显着的临床异质性，我们参与了一项合作工作，以确定 VEXAS 生存的独立预测因子并了解这些因素的机制基础。我们分析了 83 名在 p.Met41 (p.Met41Leu/Thr/Val) 处存在 UBA1 体细胞致病性变异的患者，该变异是 UBA1 (UBA1b) 细胞质亚型翻译的起始密码子。具有 p.Met41Val 基因型的患者最有可能患有未分化炎症综合征。多变量分析显示耳软骨炎与生存率增加相关，而输血依赖和 p.Met41Val 变异与生存率下降独立相关。使用体外模型和患者来源的细胞，我们证明 p.Met41Val 变体支持比 p.Met41Leu 或 p.Met41Thr 更少的 UBA1b 翻译，为生存率降低提供了分子原理。此外，我们还表明，这三个典型的 VEXAS 变体比该密码子内其他六种可能的单核苷酸变体产生更多的 UBA1b。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新的 UBA1 顺式突变。在报告基因检测中，一种突变（c.121 A>T；p.Met41Leu）导致 UBA1b 翻译严重降低，但与第二种突变（c.119 G>C；p.Gly40Ala）共表达可将 UBA1b 水平恢复到的规范突变。我们得出的结论是，残余 UBA1b 翻译的调节是 VEXAS 综合征发病机制的基础，并有助于疾病发病机制。在本报告期内，报告这些发现的手稿以电子方式发表在《Blood》杂志上。全身性幼年特发性关节炎（sJIA；斯蒂尔病）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 名 sJIA 患者进行的病例/对照研究的分析，这些患者表现出对白细胞介素 1 (IL) 抑制剂的药物反应，包括嗜酸性粒细胞增多和全身症状 (DRESS) -1) 或 IL-6，与 65 名耐药 sJIA 对照进行比较。对所有 sJIA 受试者的临床数据进行了回顾性分析，并对 94/131 的受试者进行了 HLA 分型。欧洲 sJIA-DRESS 病例的血统与国际儿童关节炎遗传学联盟 (INCHARGE) 儿科 sJIA 病例 (n=550) 相匹配，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) 进行比较，对 HLA 关联进行了分析。川崎病受试者（n=19）也进行了类似的研究。 sJIA-DRESS 特征包括嗜酸性粒细胞增多 (89%)、AST-ALT 升高 (75%) 和非消失性皮疹 (95%)。 sJIA-DRESS (64%) 与耐药 sJIA (3%；p=1.2x10e-14) 相比，治疗期间巨噬细胞激活综合征很常见。与 INCHARGE sJIA 对照 (p=7.5x10e-13) 和自我鉴定、血统匹配的 sJIA 对照 (p=6.3x10e-10) 相比，sJIA-DRESS 病例中的 HLA-DRB1*15 单倍型显着富集。在川崎病队列中，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，并且与常见的 HLA-DRB1*15 单倍型密切相关，我们建议考虑处方 HLA 分型并对严重反应保持警惕。报告这些发现的手稿已在本报告期内发表在《风湿病年鉴》上。