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Genomics of Vaccine -Induced Myocarditis
Bruce Carleton
Professor and Chair, Division of Translational Therapeutics, Department of Pediatrics,
Professor of Pediatrics, Medical Genetics, Pharmaceutical Sciences, Population and Public Health
University of British Columbia
Clinical Pharmacology Lead, MedSafe Clinics, BC Children’s and St Paul’s Hospitals
Senior Clinician Scientist, BC Children’s Hospital Research Institute
Vancouver, Canada
Dr.Carleton has received financial support forgenomics research from the
following government and non -profit sources:
Canadian Institutes ofHealth Research, Genome Canada, Genome British
Columbia, Genome Alberta, Génome Québec, Ontario Genomics, Health Canada,
BCChildren’s Hospital Foundation, BCProvincial Health Services Authority ,
Michael Smith Foundation for Health Research, USCenters forDisease Control
andPrevention , and the Coalition for Epidemic Preparedness Innovations (CEPI) .
The work today was funded by a grant to the Global Vaccine Data Network (GVDN)
provided by the US Centers for Disease Control.
Heisapast consultant totheUnited Health Group , Dynacare Next Specialized
Diagnostics andNeopharm Labs regarding pharmacogenetic testing.
This work was
funded by a grant
to the Global
Vaccine Data
Network (GVDN)
Steve Black MD, Helen Petousis -Harris PhD, Jim Buttery MD
Co-Directors
the GVDN:
A collaborative Network of 32 countries and growing
Argentina
Australia
Brazil
Canada
Chile
China
Denmark
EnglandEthiopia
Finland
France
Ghana
Hong Kong
India
IndonesiaJapan
Korea, Republic of
New Zealand
Scotland
Taiwan
USA
VAC4EUSouth Africa
and the
Alive collaboration
countries: DRC Congo
Ethiopia, Ghana,
Kenya, Malawi,
Mali, Mozambique,
Nigeria , Rwanda
COVID -19 mRNA Vaccine -induced Myocarditis
Exome Sequencing Cohort
Clinical Elements for Brighton Collaboration Level 1 Myocarditis Cases ( N=50)
Age, [Mean (SD); range]
[Median; IQR]26.5 (13.5); 11 to 83 yr
21.5 yr; 18 to 31 yr
Biological sex, n (%) Male ( n=40, 80%), Female ( n=10, 20%)
Self-reported ancestry, nEuropean ( n=31); Australian ( n=7);
Unknown (not reported) ( n=7); Egyptian ( n=1);
Lebanese ( n=1); Admixed American ( n=1);
Indian ( n=1); South African ( n=1)
Vaccine manufacturer, n (%) Pfizer ( n=37, 74%); Moderna ( n=13, 26%)
Dose, n (%)1st does ( n=10, 20%); 2nd dose ( n=36, 72%);
3rd dose ( n=4, 8%)
Vaccination to onset of myocarditis
symptoms, [Median; IQR]*4 days; 3 to 26
*available for 30 patients only
Methods
•50 Brighton Collaboration Level 1 myocarditis cases were sequenced
•Exome -captured library preparation was sequenced with the Illumina
NovaSeq 6000 system, reaching an average depth of 100x
•Reads were aligned to the GRch38 human reference genome
•49 of 50 samples passed the quality control process
•Examine variant frequencies ≥ 50% in cases when global allele
frequency ( ClinVar ) is ≤ 15%
7 variants across four genes identified with
clear linkage to myocarditis development
No. Gene Function SNP IDMinor allele
frequency (n=49)Global allele frequency
(n=5,008)Fisher's exact
P-valueOdds ratio
(95% CI)
1 LRP8 Missense rs5174 0.398 0.144 (T) 9.58x10-10 3.92 (2.53 - 5.99)
2 VKORC1 Intron rs2884737 0.306 0.0914 (C) 2.44x10-9 4.38 (2.74 - 6.87)
3 AGTR1 3 Prime UTR rs5186 0.327 0.118 (C) 5.34x10-8 3.63 (2.29 - 5.64)
4 ACAN Missense rs3817428 0.316 0.114 (G) 9.56x10-8 3.59 (2.25 - 5.60)
5 SUMF1 Missense rs2819590 0.306 0.117 (T) 5.24x10-7 3.34 (2.09 - 5.23)
6 WDR62 Synonymous rs2301734 0.316 0.125 (A) 6.93x10-7 3.24 (2.04 - 5.05)
7 TTN Missense rs36051007 0.316 0.126 (T) 8.22x10-7 3.21 (2.02 - 5.00)
8 TTN Missense rs35833641 0.316 0.127 (G) 9.74x10-7 3.18 (2.00 - 4.96)
9 ANHX Missense rs36146434 0.316 0.129 (C) 1.40x10-6 3.12 (1.96 - 4.86)
10 ALPP Missense rs1048988 0.327 0.141 (C) 3.02x10-6 2.96 (1.87 - 4.60)
11 TTN Missense rs12463674 0.310 0.130 (G) 3.25x10-6 3.01 (1.89 - 4.68)
12 EDARADD 3 Prime UTR rs6428955 0.316 0.138 (T) 5.75x10-6 2.90 (1.82 - 4.51)
13 MCPH1 Intron rs1961222 0.330 0.150 (T) 7.24x10-6 2.80 (1.78 - 4.32)
14 MSH6 Missense rs1800935 0.306 0.135 (C) 1.12x10-5 2.82 (1.77 - 4.42)
15 CHRNA5 Missense rs16969968 0.316 0.150 (A) 4.47x10-5 2.63 (1.65 - 4.10)
16 SUGP1 Stop Gained rs11555053 0.306 0.149 (A) 8.74x10-5 2.52 (1.57 - 3.94)
17 VPS53 Missense rs11558129 0.296 0.145 (A) 0.000138 2.47 (1.54 - 3.88)
18 TTN Missense rs12464787 0.296 0.147 (A) 0.000152 2.45 (1.53 - 3.84)
An increase in the number of homozygous risk
variants shortens the time to onset of myocarditis
LRP8 (LDL Receptor Related Protein 8)
•Expressed in the heart, endothelium, vascular smooth muscle, and
platelets
•R952Q variant (rs5174) is linked to cardiovascular inflammation and
immune response, particularly in coronary artery disease (CAD) and
myocardial infarction (MI) (OR: 1.31 –1.42, P<0.05)
•Among 49 Brighton Level 1 myocarditis cases, 10 are homozygous for
the risk allele (TT) and 19 are heterozygous (CT) for rs5174.
AGTR1 (Angiotensin II Type 1 Receptor)
•Patients with AGTR1 rs5186 risk CC genotype display both increased
LDL and triglycerides
•AC and CC genotypes are associated with ≥90% left anterior
descending artery stenosis [OR: 1.94 (1.059 -3.552, P=0.032)].
•The C allele is associated with MI susceptibility [OR:1.12 (1.01 -1.25);
P=0.03] and essential arterial hypertension severity ( P=0.033).
•Among 49 Brighton Level 1 myocarditis cases, 4 are homozygous for
the risk allele (CC) and 24 are heterozygous (AC) for rs5186.
LRP8 & AGTR1 in Renin -Angiotensin System (RAS)
AGTR1
rs5186
Angiotensin II
Hypertension;
Vasoconstriction;
Cardiac hypertrophy
Ref: Curr Treat Options Oncol. 2024;25(11):1406 -1427ApoELRP8
rs5174
p38 MARK pathway
activation
Cardiovascular
inflammationApoE
VKORC1
(Vitamin K Epoxide Reductase Complex Subunit 1)
•Highly expressed in the heart
•Key element of vitamin K signaling and warfarin dosage
•The rs2884737 C allele is associated with increased sensitivity to
warfarin dose compared to the wild -type A allele
•VKORC1 haplotypes are associated with arterial vascular diseases
(e.g., stroke, coronary heart disease, and aortic dissection)
•Among 49 Brighton Level 1 myocarditis cases, 3 are homozygous for
the risk allele (CC) and 24 are heterozygous (AC) for rs2884737
VKORC1
Ref: Pharmacol Rev. 2013;65(3):987 -1009VKORC1
risk haplotypes
Prevent vascular calcification
Prevent atherosclerosis
TTN (Titin)
•TTN variants are the most frequent cause of dilated cardiomyopathy
and account for 25% of familial and 18% of idiopathic cases
•TTN is associated with acute myocarditis, with a higher variant
prevalence in cases (6%) than in controls (1% -2.9%) ( P=0.019).
•Among 49 Brighton Level 1 myocarditis cases, 3 are homozygous for
all four variants, 2 are homozygous for three variants, and 21 are
heterozygous for all four variants.
Consequences of TTN variants
TTN variants
Ref: Nat Rev Cardiol . 2018;15(4):241 -252.
Planned Next Steps
•Before the GVDN grant was cancelled
oGoal: 275 cases per each adverse event
and 2,750 controls per vaccine
platform (a total of 5,500 controls for
both mRNA and adenoviral vector -
based platforms)
•Further analysis and verification of the exome sequencing data
•Genome -wide analysis for the full cohort of myocarditis (+/ - pericarditis and
myopericarditis) will be conducted once the target enrollment is reached
•Exome analysis of vaccine -induced immune thrombotic thrombocytopenia (VITT) will be
conducted in a subset of patients with the highest certainty of being vaccine -induced
•Genome -wide analysis for the full cohort of VITT will be conducted once the target
enrollment is reached. Adverse event Expected # Enrolled #
Myocarditis 422 207 (195 mRNA)
Pericarditis 301 47 (39 mRNA)
Myopericarditis 273 36 (32 mRNA)
VITT 235 81 (51 AVV)
GBS 154 37 (27 AVV)
Control 4,9601,967 (1,005 mRNA & 804
AVV)
A final word about vaccine genomics
•Genomics studies of drugs have revolutionized drug
therapy allowing for personalized approaches to
treatment. More than 500 FDA -approved drugs have
genetic information annotated in their labels.
•Identifying genetic markers of risk for vaccine adverse
events would serve two purposes:
•Facilitating a better understanding of the
pathophysiology of events
•Allow for personalized vaccine schedules that
reduce the risk of AEFIs.
GVDN | A coordinated program of vaccine safety activities