Comprehensive genomic and inflammatory profiling of vaccine-associated myocarditis

疫苗相关性心肌炎的全面基因组和炎症分析

• 批准号: 10575187
• 负责人: Amy R. Kontorovich
• 金额: $ 25.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575187
• 关键词: ACE2; Adult; Adverse event; Advocate; Age; Alcohols; Angiotensin Receptor; Autoantibodies; Automobile Driving; Benefits and Risks; Biological Assay; Blood; COVID-19 pandemic; COVID-19 patient; COVID-19 vaccination; COVID-19 vaccine; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Child; Clinical; Complication; Coupled; Cytometry; DNA; Data; Disease; Disease model; Dystrophin; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomic approach; Genomics; Genotype; Heart; Heterozygote; High Prevalence; Human; Human Genetics; Immune; Immune response; Immune signaling; Immunologics; Immunophenotyping; Impairment; Incidence; Individual; Inflammatory; Influenza; Informatics; Injury; Institution; Integration Host Factors; Link; Marker Vaccines; Mediating; Messenger RNA; Moderna COVID-19 vaccine; Mutation; Myocarditis; Overlapping Genes; Participant; Pathogenesis; Patients; Perinatal; Pfizer-BioNTech COVID-19 vaccine; Population; Predisposing Factor; Predisposition; Principal Investigator; Process; Proteins; Provider; Public Health; Publishing; RNA vaccine; Recording of previous events; Reporting; Risk; Risk Factors; Rodent Model; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Saliva; Smallpox; Structure; Testing; Time; Vaccination; Vaccines; Variant; Viral; Visit; Vulnerable Populations; Work; adverse event risk; adverse outcome; aged; biobank; cohort; coronavirus vaccination; cytokine; exome sequencing; experience; genetic risk factor; genetic variant; health organization; high risk; human disease; improved; insight; male; predictive marker; profiles in patients; prophylactic; public database; rare variant; recruit; risk stratification; sex; single-cell RNA sequencing; stem; treatment strategy; viral myocarditis; virtual

PROJECT SUMMARY The cardiac inflammatory disorder myocarditis is a rare but important complication following vaccination against COVID-19. Other than younger age and male sex, no risk factors for this adverse outcome have been found. Recognition of host factors that predispose to vaccine-associated myocarditis (VAM) would highlight those individuals for whom the risk of vaccination may be higher than the risk of COVID-19 infection and should therefore avoid or alter vaccination. Furthermore, fundamental insights into the pathogenesis of this complication and the interaction of innate cardiac immune responses with host genetics are lacking. We previously discovered that ~16% of adults and children with idiopathic or viral myocarditis harbor rare putatively damaging variants in a set of cardiac genes. Our findings suggest that genetically-mediated impairments in the structural integrity of cardiomyocytes render them susceptible to injury by cardiotoxic agents and, therefore, such variants may similarly underlie VAM. Leading a multi-institution consortium, we will recruit 50 individuals aged ≥ 5 years with VAM and perform exome sequencing to interrogate for relevant variation in 92 myocarditis-related genes, in comparison to exome sequencing of individuals with a history of uncomplicated COVID-19 vaccination. This directed genomic approach is well-powered to identify host genetic risk factors for VAM and enable precision risk stratification to minimize potential harms in genetically vulnerable individuals. Additionally, we will perform multi-scale immunophenotyping via single cell RNA sequencing (scRNA), cytometry by time of flight (CyTOF), cytokine and autoantibody assays to uncover the pathogenesis of this condition. Comparing immune responses in those with and without susceptible genotypes will improve understanding of VAM susceptibility and new prophylactic/treatment strategies.

项目总结