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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综合症