New genetic clues reveal why some people may be predisposed to myocarditis or pericarditis after COVID-19 vaccination, offering fresh insight into immune responses and vaccine safety.

Study: Genome-wide association study of myocarditis and pericarditis following COVID-19 vaccination. Image Credit: Kateryna Kon / Shutterstock

Could your genes affect how your body reacts to a coronavirus disease 2019 (COVID-19) vaccine? Although heart inflammation after vaccination is rare, scientists have identified specific genetic variants that may increase the risk.

A recent study by a team of Swedish researchers, published in the journal NPJ Vaccines, sheds light on why some people develop myocarditis or pericarditis after receiving the COVID-19 messenger ribonucleic acid (mRNA) vaccines.

COVID-19 vaccines

Since the global rollout of COVID-19 vaccines, billions of doses have been administered to control the pandemic. While most side effects are mild, a small number of people, especially young males, have experienced heart inflammation, specifically myocarditis or pericarditis, shortly after receiving an mRNA vaccine. These conditions involve inflammation of the heart muscle or the surrounding sac, typically appearing within a week of the second dose.

Current research suggests that these rare reactions may be linked to how the immune system responds to the vaccine, especially the spike protein of the virus. However, the exact biological mechanisms remain unclear. Factors such as age, sex hormones, and pre-existing immune conditions have been proposed as contributors, but no clear genetic explanation has been confirmed.

About the study

This study was conducted using data from the SWEDEGENE-COVID19-MYOPERIC cohort, a group of 66 individuals in Sweden who developed myocarditis, pericarditis, or perimyocarditis after receiving a COVID-19 vaccine. The participants were 18 years or older and had their diagnoses confirmed by healthcare professionals based on clinical records and cardiac imaging.

Only cases assessed as definitely or possibly related to vaccination were included. Each case was carefully evaluated using World Health Organization criteria, focusing on timing, symptoms, and possible alternative explanations.

A control group of close to 5,000 individuals from the Swedish Twin Registry was also included. All participants provided blood or saliva samples and data on medical history, lifestyle, and medication use. About 41% of patients fully recovered within three months, while others experienced prolonged or incomplete recovery. Both groups underwent genetic testing using high-throughput deoxyribonucleic acid (DNA) arrays, with rigorous quality control steps to check for missing information, rare variants, and population differences.

The authors note that, because these conditions are very rare, the sample size was small, which can limit the statistical certainty and generalizability of the findings.

The researchers conducted a genome-wide association study using specialized software to find differences in DNA that might be linked to heart inflammation after vaccination. The analysis focused on identifying single-nucleotide polymorphisms (SNPs), or minor changes in DNA, that occurred more often in patients than in controls.

Each case also underwent a comprehensive medical review. Patients received various standard cardiac tests, such as electrocardiography, echocardiography, and cardiac magnetic resonance imaging (MRI). Lab tests were performed to check for markers of inflammation and heart injury. Medical histories were also analyzed to understand other health conditions and medications that might have contributed to their reactions.

The study’s goal was to determine if any genetic variants could be associated with these rare but serious reactions. This could lead to personalized vaccine strategies and a better understanding of the immune response to mRNA vaccines.

Major findings

The study found that specific genetic variations may increase the risk of developing heart inflammation after receiving a COVID-19 mRNA vaccine. In patients who developed pericarditis or perimyocarditis, three genetic variants located near the SCAF11 gene were strongly associated with the condition. These variants, identified as rs536572545, rs146289966, and rs142297026, were much more common in affected individuals compared to the general population.

The SCAF11 gene is involved in pyroptosis, a form of cell death that causes intense inflammation. This connection suggested that individuals with certain versions of this gene may experience an exaggerated inflammatory response to the vaccine. These findings were especially strong in individuals who received the Comirnaty or Spikevax vaccines, which are both mRNA vaccines. No significant genetic associations were found when looking at individual vaccines other than Spikevax for myocarditis, and for the SCAF11 gene, no significance was observed when stratified by individual vaccine.

For myocarditis, a different variant – rs570375365 in the LRRC4C gene – was significantly associated with cases that occurred after Spikevax vaccination. This gene is known to play roles in immune signaling and has been linked to both heart and brain function. Variants in LRRC4C have also been associated with susceptibility to and severe outcomes of COVID-19 in previous studies.

Despite their similar clinical features, these genetic findings point to different biological pathways underlying myocarditis and pericarditis. The study’s authors caution that odds ratio (OR) estimates for these rare genetic variants should be interpreted carefully, as statistical uncertainty is greater when there is little or no variation seen among controls. However, the small sample size and the use of available clinical information rather than globally used standardized diagnosis criteria presented some limitations to drawing generalizable conclusions. Additionally, the diagnoses were made based on clinical and imaging findings, rather than systematically applying international criteria such as those from the American College of Cardiology (ACC), European Society of Cardiology (ESC), or Brighton Collaboration, which could affect comparability with other studies. Proving a direct causal link between the vaccine and these conditions remains complex.

Conclusions

Overall, the findings highlighted a potential genetic link to rare occurrences of myocarditis and pericarditis after COVID-19 mRNA vaccination. By highlighting specific genes and inflammatory pathways, the study offered new leads for investigating why only certain individuals develop serious side effects after vaccination.

While more research is needed to confirm these findings in larger groups, the study marks an important step in understanding individual responses to vaccination and improving public confidence in immunization programs.