Key Takeaways
- Genetic Influence: Immunogenetics explores how individual genetic variations (polymorphisms) dictate how our immune systems respond to COVID-19.
- Long COVID Prevalence: While most recover quickly, approximately 28% of patients experience long COVID, involving over 200 symptoms across various organ systems.
- Specific Genetic Markers: Variants near the FOXP4 gene and specific HLA system alleles have been linked to increased susceptibility and symptom severity.
- Drug Discovery: Recent studies have identified 73 genes associated with long COVID, 42 of which are potential targets for new pharmaceutical treatments.
- Personalized Care: Research is shifting the medical approach from general symptom management toward tailored, gene-based therapies.
What is immunogenetics?
Immunogenetics is the study of the genetic components that shape our immune system, the body's defense mechanism against infections and diseases. It examines the interplay between our genes and immune response, both in normal health and during disease. Understanding this interplay is central to explaining why individuals respond so differently to the same pathogen.
Genetic polymorphisms, variations in our genes that make each person genetically unique, are foundational to immunogenetics. These polymorphisms, particularly in immune-related genes, influence how our immune system operates. Even slight variations can alter how the body detects, responds to, and clears a pathogen.
For biotech and pharmaceutical companies, this has direct implications. Understanding which polymorphisms affect immune response informs vaccine design, treatment development, and the creation of personalized therapies tailored to an individual's genetic profile.
In a recent study, the genetic elements controlling the immune system were highlighted as some of the most polymorphic loci in our genome. This means that the genes governing immune responses are highly diverse, and even slight variations can impact how our immune system functions. Because of this genetic diversity, researchers are investigating how these variations affect immune responses to viral infections, including COVID-19.
Immunogenetics and long COVID
In the context of COVID-19, both innate and adaptive immune responses come into play. The innate response provides the initial line of defense, detecting and reacting to the virus, while the adaptive response involves creating antibodies and immune cells targeting the virus.
COVID-19 can disrupt the immune system through several mechanisms. A hyperactive immunological reaction, known as a cytokine storm, can occur, where the immune system produces excessive cytokines, causing widespread inflammation and potentially fatal consequences. Alternatively, COVID-19 may inhibit the immune response, particularly in older adults and those with underlying health conditions.
Beyond these acute effects, several theories have emerged to explain why some individuals develop long-term illness:
- The virus may trigger autoimmune reactions, where immune cells mistake the body's own cells as threats
- COVID-19 may reactivate dormant viruses that the body has not fully cleared
- The infection may disrupt the gut's microbial ecosystem, with the virus potentially persisting in the gut
- The virus may damage the cells lining blood vessels or affect communication in the brain stem and vagus nerve
These mechanisms are not mutually exclusive and may interact differently depending on an individual's genetic profile.
Long COVID affects around 28% of people who get COVID, with over 200 symptoms impacting various organ systems. Critically, individuals can develop long COVID regardless of how sick they felt during the acute infection, including those who were asymptomatic or never received a formal diagnosis. This variability underscores the importance of understanding the genetic factors at play. Research is actively working to understand the ways genetic variations in immune-related genes might contribute to the observed heterogeneity in long COVID.
- A study comparing patients with long COVID to uninfected individuals and those without long-term symptoms revealed distinct immune differences at around 14 months post-infection. Notable changes included increases in non-classical monocytes, activated B cells, and specific T cell subtypes, along with decreased conventional dendritic cells and exhausted T cells. Separate research into B-cell responses in long COVID patients has identified reduced frequencies of memory B cells and impaired antibody responses in those with persistent symptoms."
- The COVID-19 Host Genetics Initiative, through a genome-wide association study, identified a variant near the FOXP4 gene that was also associated with long COVID. This gene, expressed in the lungs and some immune cells, was previously linked to COVID-19 severity. The variant's stronger impact on long COVID indicating its role in the prolonged nature of the illness, particularly in symptoms such as shortness of breath and persistent cough.
- Researchers have also discovered that deficiencies in type 1 IFN immunity elevate the risk of critical COVID-19 pneumonia and that polygenic risk scores linked to fatigue also indicate susceptibility to long COVID. Researchers at the University of Sheffield and Stanford University have pinpointed specific genetic signals, mainly in NK cells and T cells, accounting for 77% of the observed heritability associated with increased severity of COVID-19.
- Investigations into the genetic factors influencing COVID-19 susceptibility and severity have brought attention to variants in the ACE2 receptor and TMPRSS2 gene. These proteins are crucial for viral entry into human cells, with ACE2 serving as the receptor for the virus and TMPRSS2 facilitating the activation of viral particles. Despite the association of certain genetic variations with COVID-19 severity, research involving 293 previously hospitalised COVID-19 patients found no direct link between four genetic variants related to ACE2 and TMPRSS2 genes and Long COVID symptoms. This discrepancy underscores the complexity of the disease and the need for further research to understand the genetic basis of Long COVID.
- The Human Leukocyte Antigen (HLA) system, which is integral to the immune response against viral infections, also demonstrates significant variability in the context of COVID-19. Variants within the HLA genes can influence an individual's susceptibility to the virus and the severity of their response. For instance, the HLA*B15:03 allele has been associated with a higher likelihood of asymptomatic COVID-19 infections, pointing to a genetic basis for the variability in disease manifestation. This highlights the importance of the HLA system in understanding individual differences in immune responses to SARS-CoV-2 and points to potential areas of investigation for long COVID.
- A grant-funded observational study conducted by Sano is examining the immunogenetic profile of a diverse long COVID cohort—combining at-home genetic testing, longitudinal participant engagement, and integrated data collection to understand biological causes, support diagnostic criteria development, and identify potential therapeutic targets. In an analysis of the data by PrecisionLife, 73 genes highly associated with long COVID populations were identified, including 42 genes that are potentially tractable for novel drug discovery approaches.
Insights from immunogenetics are expected to deepen understanding of long COVID and support the development of more personalized, evidence-based care strategies for affected patients.
Future directions in long COVID research
The research landscape surrounding long COVID is rapidly expanding, exploring the complexities of this condition to uncover why it manifests so variably among individuals. Researchers now believe that specific patterns of symptoms, called clusters, may represent distinct phenotypes of long COVID, with patients experiencing symptoms from multiple clusters simultaneously or at different times. This variability underscores the critical role of genetics and the immune system in shaping individual responses, and points toward immunogenetic profiling as a tool for differentiating these subtypes.
Currently, approximately 90 studies are underway, aiming to identify effective treatments for long COVID. These efforts, however, are in their nascent stages and will require time to yield clinically actionable insights.
The approach to managing long COVID, for now, remains symptomatically focused, adopting a holistic strategy that addresses the multifaceted nature of the condition. Treatments being explored include the use of compression stockings, physical therapy, activity pacing, flexibility and strength training, and specific medications tailored to alleviate symptoms. On the preventive side, evidence indicates that COVID-19 vaccination may help reduce the risk of developing long COVID, adding another dimension to the public health response.
Despite these advancements, the essence of treating long COVID will likely continue to necessitate a multidisciplinary, team-based approach. Such an approach integrates the expertise of various healthcare professionals to address not just the physical aspects of the condition, but also the psychological, social, and rehabilitative needs of patients.
Conclusion
Long COVID is now recognized as a serious illness that can result in chronic conditions and, in some cases, disability. It represents one of the most significant ongoing challenges of the COVID-19 pandemic. Immunogenetics is essential to explaining why individuals respond so differently to the same virus, and its role in shaping the next generation of research and treatment will only grow.
As the genetic differences that determine susceptibility to prolonged symptoms become clearer, the trajectory for long COVID treatment is shifting from a one-size-fits-all approach toward therapies stratified by individual genetic and immune profiles. This direction in research has the potential to improve both the management of long COVID and our broader understanding of how genetics shapes immune response to disease.