The Genetics of Long COVID

In 2020, the world as we knew it changed. The COVID-19 pandemic began as a localized outbreak in Wuhan, China, but rapidly evolved into a global crisis that still presents healthcare challenges years later. Variant strains have evolved with reduced lethality but increased transmissibility, and now the SARS-CoV-2 virus is endemic in the worldwide human population. While the worst days of the pandemic may be considered behind us, COVID-19 remains an issue of the present and future.

There is a large global cohort of patients for whom the pandemic casts a long shadow, with symptoms of acute COVID-19 that have never quite left, despite them being free of detectable infection [1].

This so-called ‘long COVID’ is a unique long-term disease that limits the quality of life of those it affects and is elusive in its pathology and origins.

In this blog, we discuss the genetic sequencing technologies and advancements that have already helped pave the way to better understanding COVID-19 disease pathology, and may also help us unlock the secrets of why some are more susceptible to long COVID than others.

Figure 1. Visualization of a SARS-CoV-2 virion

Acute COVID-19 Pathology and Epidemiology

COVID-19 is characterized by many symptoms common to respiratory coronaviruses and contains sequences in its genome homologous to other coronaviruses [2]. Symptoms can include:

• Fever
• Continuous coughing
• Loss or change in sense of smell and/or taste
• Shortness of breath
• Sore throat
• Congestion
• Exhaustion
• Myalgia
• Neuralgia
• Reduced appetite
• Nausea, sickness, and diarrhea

Although most acute cases of infection resolve after a few days of illness, others may take up to 12 weeks before a full return to normal [3]. While a majority of cases only involve mild illness, approximately 5% of all cases lead to critical illness [4]. However, it is not just these critical cases that lead to long COVID. Approximately 10% of all cases globally lead to some form of long-term disease, characterized by a range of pathologies from mild symptoms to disabling and life-limiting afflictions [5].

The heterogeneous nature of long COVID cases [6] can often make it difficult to identify, though fatigue, breathlessness, neurological and cognitive impairment, and dysautonomia (i.e., reduced autonomic function) are common symptoms [5]. Other milder acute symptoms may also persist in any combination.

Long-term damage to tissues in areas affected during the initial acute infection, such as the brain, heart, and lungs, may explain these long-term symptoms. It is possible that this damage is caused and exacerbated by pathological inflammation [7].

Long COVID can therefore be a debilitating condition that can greatly reduce quality of life and limit patients in their capability to work and socialize. Understanding the genetic risk factors for long COVID has the potential to create opportunities for personalized treatments and preventative strategies.

Genetic Components of Long COVID Pathology

Immunological responses like inflammation cannot fully account for all cases of long COVID, and there may be other factors at play [7]. It has been well-established that genetic markers can be used to not only identify susceptibility to a wide range of diseases, but also and vaccinations, known as pharmacogenomics [8].

Some Human Leukocyte Antigen (HLA) alleles have been identified as being associated with increased susceptibility to COVID. These, along with increased expression of C-reactive protein genes, are indicative of increased risk of developing long COVID [9]. Interestingly, there are also several introns across a variety of genes that have been linked to increased or decreased disease susceptibility and severity [10].

Moreover, there are various alleles of cytokine genes that are associated with the onset of major disease complications like cytokine storms and venous thrombosis [11]. Proinflammatory cytokines are produced to help combat infection, but their expression can continue even after acute infection has resolved. The persistence of viral particles in the body, in combination with the hyperproduction of proinflammatory cytokines, has been identified as a potential basis for this chronic condition [12].

Other immune-associated genes have also been identified that confer a high risk of severe COVID-19 symptoms and subsequent long COVID, including six genes and a cluster of alleles at locus 3p21.31 [12].

Additionally, mutations in key immune response genes, including toll-like receptor and interferon-encoding genes, have been linked to critical pneumonia in 3% of COVID-19 patients, with as many as 20% of all severe COVID-19 cases being linked to interferon circuit defects [11].

These studies demonstrate how important it is to establish links between biomarkers and disease pathology and response to interventions.

Methods to Assess the Genetic Risk Factors of Long COVID

Access to next-generation sequencing (NGS) and modern bioinformatics have been critical in identifying biomarkers associated with the risk of long COVID. Something that may not have been possible in the early 2000s.

It is typical for studies to use one or more sequencing approaches, such as:

• Whole genome re-sequencing — can be used to identify mutations in patient and pathogen genomes
• De novo sequencing — can be used to sequence novel genomes where there is no available reference, such as in the case of emerging novel pathogens
• Low-pass whole genome sequencing — ideal for high throughput sequencing when examining genetic variation
• Target region sequencing — for focusing on specific subsets of genomic regions associated with disease pathology
• Exome sequencing — for focusing on coding regions of the genome most likely to affect disease pathology

Bioinformatic techniques have also provided invaluable data on the SARS-CoV-2 genome. Tracking emerging variants has indicated that the virus mutates relatively infrequently compared to other coronaviruses, with approximately 33 genomic mutations per year. However, even single point-mutations have the potential to affect the severity and progression of symptoms, infectability of the virus, and effectiveness of vaccines. This highlights the need for robust sequencing and data analysis methods, as sequencing errors could lead to the misidentification of false variants or missing new variants altogether [13].

In addition to NGS, long-read sequencing methods are enabling routine high-throughput examination of pathogen genomes. Since its advent, PacBio’s HiFi sequencing has made long-read sequencing more accurate and cost-effective. These technologies have reduced the cost-per-base to a point where sequencing is accessible and reliable for assembling larger genomes, and will play a key role in global monitoring and responses to outbreaks in the future [14].

Genomics in Therapies for Long COVID

An understanding of a pathogen’s genomics naturally leads to new ideas and approaches for how we might combat it. Cell and gene therapies, which rely on a deep understanding of disease genomics, have been proven as effective strategies for treating many chronic health conditions, and there are promising signs that similar strategies could be employed to alleviate the symptoms of long COVID.

For example, stem cell (SC) therapies have potential to mitigate the neurological symptoms of long COVID. They could be used to suppress the genes involved in inflammatory responses and activate genes that encode neuroprotective proteins [15]. This approach could help to alleviate the long-term damage caused to tissues by prolonged immune responses [12].

The preventative measures employed during the pandemic also rely heavily on genomics. The mRNA vaccines developed at record pace were the first such vaccines to be administered, and could only be created with the use of modern sequencing technologies and analysis [16].

Just as an individual’s genetics can influence their response to pathogens, it can also influence their response to drugs and therapies (their pharmacogenetics). This includes the efficacy of different vaccines, and the strength and duration of conferred immunity. In the case of a SARS-CoV-2 infection, this can lead to genetically distinct immune reactions from person to person, and may also have an effect on their likelihood of developing long COVID. With individual genetics in mind, in future, vaccine administration could be personalized to tailor the most effective option to each patient [17].

Conclusions — Not So Long COVID?

Although long COVID presents a unique challenge in modern medicine, it is not an insurmountable one. Modern genomics tools have been essential in unlocking the SARS-CoV-2 genome and in developing therapeutic techniques to prevent and combat acute and chronic COVID-19 pathologies.

Modern genomics has also made it possible to develop vaccines to mitigate the symptoms of acute infections, and investigate novel gene therapies to disrupt viral RNA in a fraction of the time and at a fraction of the cost it would have taken a decade prior.

Through a better understanding of the genetic basis of long COVID susceptibility and severity, clinicians are developing a knowledgebase to better assess patient risk factors and create individualized treatments for best possible clinical outcomes.

At Eremid^®, we support groundbreaking genomics research. We are one of the most capable genomics laboratories in North America, and our CLIA-certified, CAP-accredited genomics lab and highly experienced staff are ready to support your next clinical genomics study.

References

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