Human genetics of myocarditis: overall, after mRNA COVID-19 vaccination, and after SARS-CoV-2 infection

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Hypothesis generation (including signal detection)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Case-control

Study drug and medical condition

• Medicinal product name:
  COMIRNATY
• Study drug International non-proprietary name (INN) or common name:
  COVID-19 MRNA VACCINE (NUCLEOSIDE-MODIFIED)
• Anatomical Therapeutic Chemical (ATC) code:
  (J07BN01) covid-19, RNA-based vaccine

  covid-19, RNA-based vaccine
• Medical condition to be studied:
  Myocarditis

Population studied

• Short description of the study population:
  The study will include the below three cohorts of cases. ; • Cohort A – post-mRNA COVID-19 vaccination myocarditis cases: myocarditis within 14 days of mRNA vaccination ; • Cohort B – post-SARS-CoV-2 infection myocarditis cases: myocarditis within 8 weeks of SARS-CoV-2 infection; • Cohort C – acute/viral myocarditis cases: myocarditis unrelated to COVID-19 vaccination or SARS-CoV-2 infection; Controls will be individuals without myocarditis who previously consented to participate in the HRN. ; Participants previously consented to be in the HRN research study and the HRN myocarditis registry sub-study between March 2018 and July 2025. After consent, participants submitted a sample for sequencing. ;
• Age groups:
  • Adolescents (12 to < 18 years)
  • Adults (18 to < 65 years)

    • Adults (18 to < 46 years)
    • Adults (46 to < 65 years)
  • Adults (65 to < 75 years)
• Estimated number of subjects:
  10000

Study design details

• Study design:
  This is a retrospective case-control genetic association study where patients with myocarditis (cases) and patients without myocarditis (controls) will be identified using the Helix Research Network (HRN) Myocarditis Registry. Cases and controls will be individuals who previously consented.
• Main study objective:
  To identify genetic variants associated with myocarditis among three populations (after mRNA COVID-19 vaccination, after SARS-CoV-2 infection, and acute/viral myocarditis unrelated to COVID-19 vaccination or SARS-CoV-2 infection) by performing a retrospective case-control study evaluating: ; a) The role of rare coding variants using a genome-wide approach by testing if rare loss-of-function or missense variants predicted to be damaging in one or more genes are more prevalent in cases of myocarditis after mRNA COVID-19 vaccination compared to controls.; b) The role of HLA alleles by testing whether an HLA allele is significantly enriched among cases versus controls (using HLA class I genes and four HLA class II genes - HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1).; c) The role of common variants by conducting a genome-wide association analysis to examine if any common variants are significantly enriched among cases compared to controls. ; d) The role of rare coding variants in 3 sets of candidate genes (CD36, IL1 pathway, cardiomyopathy genes) that have each been linked to myocarditis in the literature.;
• Setting:
  This study will mostly use the US-based HRN Myocarditis Registry, originally consisting of electronic health records (EHR), case report forms (CRF), questionnaire, and genetic (whole exome sequencing) data on individuals with and without myocarditis. The data was collected from participants who consented to the HRN protocol between 1 April 2018 and 25 July 2025 and provided saliva, buccal, or blood samples for germline Exome+® sequencing. Additionally, select pediatric participant data may be incorporated from a secondary pediatric study under a data sharing agreement. ; ; The HRN study is an umbrella encompassing multiple research projects led by Helix and the following health systems in the US: Renown Health, HealthPartners, the Medical University of South Carolina, WellSpan Health, Nebraska Medicine, St. Luke’s University Health Network, Sanford Health, and the Ohio State University. To construct the HRN Myocarditis Registry specifically, Helix previously reached out to physicians and healthcare organizations (members of the HRN and additional new contacts) to identify potential myocarditis cases. ; Sequencing data from whole Exome+ sequencing was typically generated and available 3 months following consent and return of a biological sample from the participants. Phenotype data including electronic health records data was updated on a quarterly basis for participants part of the HRN study and data from the data freeze of October 2025 will be used for this analysis. Data collected via eCRF was collected once for cases only, after a myocarditis diagnosis and between 2023 and 2025. ;
• Comparators:
  Not applicable.
• Outcomes:
  The outcome of interest is the diagnosis of myocarditis (Myocarditis after vaccination, Myocarditis after SARS-CoV-2 infection and Myocarditis not related to COVID-19) and the key covariates include age, sex, vaccine dose, and other known risk factors. ;
• Data analysis plan:
  A variety of genomic analysis methods will be executed, including a genome-wide rare-variant, genome-based analysis (to identify rare variants), an HLA analysis, and a genome-wide association study (to identify common variants). ; ; To address the Primary Objective, whole exomes were processed through a bioinformatic pipeline in order to generate an analysis-ready genomic dataset. Using exome data, various genetic analyses will be performed, including rare-variant gene-based collapsing analyses (to identify rare variants), HLA-WAS (to investigate beyond simple single nucleotide polymorphisms in the HLA region), GWAS (to identify common variants), and a candidate gene approach to investigate specific genes and pathways including CD36, the IL1 pathway, and cardiomyopathy genes. Descriptive statistics will be presented to characterize patients (cases and controls) in terms of demographics and clinical characteristics at the time of the index myocarditis diagnosis.