COVID-19 and Genomics

Genetic variation, something beyond classic comorbidity?
“COVID-19” illness caused by the SARS CoV-2 virus has such a variety of symptoms when they contract it. It is said that “comorbidity” (other prior health conditions) are the reason some have mild illness and some severe illness. This is likely true, but we also see people with no known comorbidity who have very severe illness or even die from the virus. Likewise, some with comorbidities do not seem to suffer as bad with the infection as others with their same comorbidity.

It seems logical then that genetics may play a role in this variety of disease, as they do in so many other diseases. It is also important to consider that genetic differences are both in the person (disease host) as well as the virus.

Below we will look at what we currently know about genetics and COVID-19. Of course, we know that we do not know everything about this virus or certainly its genetics, so this is simply what we know now and how it can apply to this viral disease.

Just for background, genotype refers to the genetic characteristics of humans (in this case) and phenotype refers to physical characteristics or expression. And because of epigenetic influences (those that regulate genes) genotype is not always expressed as phenotype.

WHAT DO WE KNOW?
Keeping in mind this is a rapidly evolving situation and we only “know what we know” as of today, the science as it stands is showing us that we have genetic variation in the virus affecting its severity as well as genetics in the human affecting the human experience of the disease. I will look at the science of viral genetics first then those of us humans.

An unhappy family; SARS, MERS, COVID-19…

A genetic and epidemiological review done by Sironi et. Al [1] provides an excellent overview of this evolving work.

They note: “Genomic epidemiology of the virus is allowing a “live” monitoring of the viral spread and has revealed differentiation in several lineages, some clearly resulting from ongoing local circulation, which also show the frequent exchange across borders even from distant countries and continents. Globalization shows its dark side in this fast spreading pandemic.
There are substantial differences in the natural history of infection. These were observed from the very start of the epidemic, with a much more severe presentation in aged persons and those with additional pathologies. Those differences have persisted but, as the number of infected persons has grown continuously, the cases of serious, even fatal, infections in younger persons have become more frequent.

Nevertheless, there are still many unknowns around the differences in susceptibility, progression, and outcome of the infection by SARS-CoV-2 that, as in other infectious diseases, probably depend on a complex interaction of host, pathogen, and environmental factors. Several largescale analyses encompassing all three kinds of factors are underway and hopefully will shed light on this critical point.”

Six kinds of COVID?
COVID-19 has so many ways it manifests in humans from mild illness to fatal illness (have we not all thought “COVID seems so variable, some people get digestive illness, some fever and pneumonia and some completely different symptoms…). Is there a correlation to viral genotypes and the expression of disease in humans? If so, does that relate to a predictable severity? In a landmark study of 2700 people with COVID-19 titled “Symptom clusters in Covid19” Sudre, et.al. [2] show SIX symptom clusters that were reproducible and related to disease presentation and severity. They showed that several demographic and health parameters were associated with a higher risk for severe respiratory disease. Of the six subtypes, they showed a great variety in the rate of hospitalization and severity of disease between the six groups.

So COVID-19 has at least six different groupings of symptom presentations and this variety is likely due to an interplay between the genetics of both the virus and the human.

Isn’t COVID-19 mutating and what does that mean for us?

In a genomic review of COVID “Real-life implications of the global shift of D614 to G614 variant” Yong [3] speaks to one major genetic change in the virus. “D614G mutation in SARS-CoV-2 is infamous for its rising dominance worldwide… The initial D614 is now the G614 variant. The question is: What real-life implications do this mutation or G614 variant bring?”

More transmissible? Probably not.

Nathan D. Grubaugh, of the Yale School of Public Health, and co-workers remarked that such studies suggest, but not prove, increased viral transmissibility. [https://doi.org/10.1016/j.cell.2020.06.040] Their review noted that: Increased viral shedding or RNA does not reflect viral transmission capacity. Cell culture work does not necessarily translate to humans. But is it deadlier?

Yong reports: “While Korber et al. found an increased viral load in patients infected with the G614 variant, there was no significant association with disease severity. Two other preprints — one investigating 175 Covid-19 patients from Seattle and the other 88 from Chicago — also did not find any relationship between the G614 variant and clinical outcomes.”

Bottom line: “The G614 variant may be more infectious, but not any deadlier than D614.”

Are there other known viral genetic factors that affect how severe it may be for humans? In an extensive paper Junejo et al. [4] discuss the ACE2 human receptor affinity to COVID and disease severity: “SARS CoV-2 uses the same receptor (ACE2) as SARS-CoV (the virus that caused SARS).” Since this receptor is the primary “entry point” for COVID a viral affinity for ACE receptors increases human disease severity.

Any good news?
Mousavizadeh et.al. [5] In confirming something we already knew about SARS and COVID-19 “Notably, these observations in COVID-19 patients are similar to those who suffered from severe acute respiratory syndrome (SARS) during the 2003 epidemic.” But as with other viruses is it moving toward a less virulent (less severe) disease? “COVID-19 is expected to become less virulent through human to human transmissions due to genetic bottlenecks for RNA viruses…” If this continues to play out it will truly be a good trend.

Human genes that may protect or increase disease severity…

Just as the genetics of the virus can cause more or less disease severity, human genetic variety can play into disease severity. A major way human genetic variety interacts with many illnesses is via an immune receptor type known as “HLA”. In a large human genome map Nguyen et.al. [6] demonstrate the important implications of these human genetic differences with COVID-19  expression. “Genetic variability across the three major histocompatibility complex (MHC) class I genes… HLA… may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2)… / (COVID-19).”
Any specific HLA that was found to be notable? “… we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS… Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity.”

This shows not only more commonality with SARS but also a variation in the potential for long term Cell Mediated (T-Cell) immunity. From this work [6] the authors synthesized the following genetics of note:
• TICAM2 codes proteins that help activate the Toll-like Receptors involved in innate immunity, our first line of defense against pathogens.
• HLA-B46:01 codes the histocompatibility (HC) proteins. Variants have fewer spaces on T cells for recognition of COVID virus and are very susceptible to increased virology and severity.
• HLA-B-15:3 a protective gene where variants have the greatest capacity to allow SARS COV2 peptidesand enable T cell immunity.
** Those who are variant for SLC6A20 and normal for ACE have a 1.77 times higher probability of being hospitalized for respiratory failure with SARS-Co-V-2.
• SLC6A20 – encodes for the amino acid transporter that interacts with the ACE2 receptor – the main receptor that SARS-Co-V-2 uses to enter a human cell.
• ACE –Variant have less ACE receptors, and thus less available “spaces” for the virus to enter.

Any other specific variants associated with respiratory disease?
Ellinghaus, et.al. [7] reveal genetic variants, rs11385942 at locus 3p21.31 and rs657152 at locus 9q34.2, associated with COVID-19 induced respiratory failure. Heterozygote (two different alleles of a particular gene) carriers for these increase the risk by 1.5 times of developing severe COVID-19 symptoms, and greatly increases the risk of a patient requiring a mechanical ventilator.

Heritable and racial differences?
In early data looking at sudden cardiac death in African Americans Giudicessi et.al. [8] show landmark information: “Taken together, these data suggest that 1 in 13 African Americans may be at a
substantially increased risk of potentially lethal [cardiac dysfunction] during the COVID-19 pandemic because of the perfect storm of (1) intrinsic genetic susceptibility (ie, p.Ser1103Tyr-SCN5A), (2) modifiable environmental risk factors (eg, electrolyte abnormalities and concurrent QTc-prolonging drug use), and (3) COVID-19–specific risk factors (eg, profound hypoxemia and cytokine storm).” We are likely to see more race – heritability data emerge which could help save lives in the severely ill.

What about some of the “nutrigenomic targets” we often hear of?

Nutrigenomics, or the use of nutrients to target and support genes epigenetically, often are used to help people with genomic issues maintain better health. Areas of detoxification, glutathione function and some immune factors are common targets. It has been proposed in many papers that the effects of Vitamin C, D, Glutathione, and other nutrients may enhance human biological function during illness and either protect from many of the disease severity factors or possibly speed recovery. [9,10,11,12]

Of nutrigenomic targets on which to focus those that affect inflammation, immune dysregulation and related functions are likely the most important to modifying disease severity, improving quality of life, and potentially saving lives. In a real-time review of confirmed COVID-19 cases and their immune signaling chemistry Ragab, et.al. [13] revealed elevated levels of IL-1β, IL-7, IL-8, IL-9, IL-10, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A, MIP1-B, PDGF, TNF-α, and VEGF in COVID-19 patients. These not only underscore what the publications noting improvement with nutrient support show [9-12 and others] but also give locations in the genome where using polymorphism testing (SNP testing) can identify targets of therapies. In a genetic variation of a SNP the gene it codes for may be faster or slower in an individual human. If those areas are in genes coding for the above immune / inflammatory factors it is possible to develop custom nutrigenomic support for a patient.

The benefit of a personalized nutrigenomic plan for a patient would be that while general use of Vitamins C and D, Glutathione, Quercetin and other nutrients are helpful, specific personalized therapy would likely be more efficacious.

SUMMARY:
What does it mean?
Genetic evaluation of people and of virus are not new, but our use of this information is ever evolving. People have asked “can this really change the clinical management of a COVID-19 patient?” With modern ability to rapidly check genomic variants the answer could be “yes”. If we see trends in the data and develop analysis tools that screen for the above (and others as they are found) it is possible to create a test yielding real world and potentially lifesaving patient specific genetic personalized medicine. Additionally, the ability to use SNP assessment and filter it through the above immune / inflammatory areas (and more as they are discovered) will allow even more benefit from nutrigenomic supportive therapies currently only used as general supportive therapies.

What can I do?

General supportive measures during prevention or treatment are still exceptionally useful. For specific uses of nutritional supports see the last newsletter “Nutrients and COVID-19 – A review of Recent Research”.

REFERENCES:
1. Sironi M, Hasnain SE, Rosenthal B, et al. SARS-CoV-2 and COVID-19: A genetic, epidemiological, and evolutionary perspective [published online ahead of print, 2020 May 29]. Infect Genet Evol. 2020;84:104384. doi:10.1016/j.meegid.2020.104384
2. Sudre, et.al. Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app. medRxiv 2020.06.12.20129056; doi: https://doi.org/10.1101/2020.06.12.20129056
3. Yong, SJ. Real-life implications of the global shift of D614 to G614 variant. What the D614G Mutation Means for Covid-19 Spread, Fatality, Treatment, and Vaccine. Jul 31, 2020. https://medium.com/microbial-instincts/what-the-d614g-mutation-means-for-covid-19-spread-fatality- treatment-and-vaccine-7dda1c066f0d
4. Junejo Y, Ozaslan M, Safdar M, et al. Novel SARS-CoV-2/COVID-19: Origin, pathogenesis, genes and genetic variations, immune responses and phylogenetic analysis. Gene Rep. 2020;20:100752. doi:10.1016/j.genrep.2020.100752
5. Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis [published online ahead of print, 2020 Mar 31]. J Microbiol Immunol Infect. 2020;S1684-1182(20)30082-
7. doi:10.1016/j.jmii.2020.03.022 6. Nguyen et.al. Human leukocyte antigen susceptibility map for SARS-CoV-2. J. Virol. doi:10.1128/JVI.00510-20 https://jvi.asm.org/content/jvi/early/2020 /04/16/JVI.00510-20.full.pdf
7. Ellinghaus, et.al. Genome wide Association Study of Severe Covid-19 with Respiratory Failure. DOI: 10.1056/NEJMoa2020283
8. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Genetic susceptibility for COVID-19-associated sudden cardiac death in African Americans [published online ahead of print, 2020 May 5]. Heart Rhythm. 2020;S1547-5271(20)30419-7. doi:10.1016/j.hrthm.2020.04.045
9. Anderson PS (2020) Intravenous ascorbic acid for supportive treatment in hospitalized COVID-19 patients J Orthomol Med. 35(1) https://isom.ca/article/intravenous-ascorbic-acid-for-supportive-treatment-in-hospitalized-covid-19-patients/
10. Cheng RZ, Kogan M, Davis D. Ascorbate as Prophylaxis and Therapy for COVID-19-Update From Shanghai and U.S. Medical Institutions. Glob Adv Health Med. 2020;9:2164956120934768. Published 2020 Jul 20. doi:10.1177/2164956120934768
11. Biesalski HK. Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship? Nfs Journal. 2020;20:10-21. doi:10.1016/j.nfs.2020.06.001

12. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect. Dis. 2020, 6, 1558−1562
13. Ragab Dina, et.al. The COVID-19 Cytokine Storm; What We Know So Far. Frontiers in Immunology DOI=10.3389/fimmu.2020.01446

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