Coronavirus Research Tracking - 12 June

Genetic pre-disposition to worse health outcomes.

In this week’s Research Tracker the focus is on research into genetic factors that may predispose people to developing severe Covid-19 symptoms.

The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre. As this is a new service, please don’t hesitate to provide feedback.

A link between dementia, apolipoprotein and Covid-19

Pre-existing dementia has been found to be a risk factor for developing severe  Covid-19 symptoms. The e4 allele of the Apolipoprotein E (ApoE) gene is associated with both dementia and delirium. Examining patient records from the UK’s BioBank a study recently published in The Journals of Gerontology: Series A found that people with the ApoE e4e4 genotype were more likely to test positive for Covid-19 than people with other ApoE alleles, and this was independent of having dementia. The link between ApoE and Covid-19 is uncertain, although ApoE has a role in the metabolism of fats and in moderating inflammatory responses.

Androgens associated with greater susceptibility to infection, or more severe symptoms

Several papers have described a correlation between higher androgen levels and susceptibility to, or severity of, Covid-19. Androgens (such as testosterone) are sex hormones, typically found at much higher levels in males than females. This aligns with observations that men often seem to be at greater risk of more severe outcomes from Covid-19. 

  • One as-yet-unpublished study has found that some small molecule drugs that reduce the expression of androgen also decrease the expression of two key cell surface proteins that help the virus infect cells. Comparing patient data the researchers also found that higher androgen levels tended to be associated with more severe Covid-19 symptoms. 

  • Research published in the Annals of Oncology found that men being treated with androgen-reducing drugs for prostate cancer appeared less likely to be infected by the virus than prostate cancer patients not receiving that treatment.

  • A Spanish study found that men with male pattern baldness (associated with high androgen levels) had a higher incidence of hospitalisation due to Covid-19 than men without the condition.

Men with higher androgen levels may have more of the cell surface proteins and enzymes that let SARS-CoV-2 infect cells. The association with more severe disease is unclear. A good summary of current evidence of the links between androgens and Covid-19 risks is provided in the 3rd June issue of Science.

Blood type may also influence disease severity

An analysis of 8.5 million single nucleotide variations across the genomes of 1,600 Italian and Spanish Covid-19 patients with respiratory failure found two sites that distinguished them from a group without Covid-19. One of these sites is within the region containing the ABO blood group gene. Patients with the “A” blood type had a greater likelihood of needing oxygen or mechanical ventilation than other blood types. Patients with the “O” blood type were less likely to require oxygen or ventilation. This study has not yet been peer-reviewed, and the marker hasn’t been pinpointed to a specific gene.

The company 23andMe reported - in a blog post rather than a scientific paper - an association between blood type and SARS-CoV-2 infection risk. They surveyed 750,000 people who have used their services to see if they self-reported Covid-19 symptoms. Their analyses indicated that people with the “O” blood group were 9-18% less likely to test positive compared to the other groups. They did not report a greater likelihood of infection for those with blood group “A”. 

The 23andMe study is ongoing, and the results need to be treated with caution because it relies on self-reporting and has only been presented in a blog post. Other studies on blood type report only an association with severity of Covid-19 symptoms, not an association with likelihood of infection.

Blood group type has been found to be associated with susceptibility to a variety of infections and diseases, although the causal links are not well understood. For example, those with blood type A can more commonly have cardiovascular diseases.

A hypothesis for why the “O” blood type may reduce the chance of more severe Covid-19 outcomes and “A” increase the risk was proposed in the European Journal of Preventative Cardiology. People with blood group “O” tend to have higher levels of interleukin-6, higher levels of ACE2 activity, and reduced levels of ACE. These may result in a reduced risk of developing very high blood pressure (hypertension) which may, in turn, reduce the effects of Covid-19. People with blood type “A” appear at greater risk of developing high blood pressure and reduced circulation (due to more white blood cells binding to blood vessel walls). Immune responses generated by Covid-19 may exacerbate these symptoms. This hypothesis requires verification.

Predisposition isn’t the whole story

The research doesn’t predict that all people with the ApoE e4e4 genotype, high levels of androgen or blood group “A” will become infected, and be badly affected by Covid-19. Those with other blood types, low levels of androgen, and ApoE alleles can also be severely affected. These genetic markers, or associations, may signify a somewhat greater potential risk, but they aren’t deterministic.

There are stronger indicators of who may be worst affected by Covid-19. Old age, hypertension, cardiovascular disease, obesity and diabetes are the conditions most strongly associated with severe Covid-19 outcomes. Accessibility to and the quality of healthcare also influence outcomes.

The ApoE, androgen and blood group research illustrate the delicate metabolic and physiological balances in the body, and how infections can co-opt or disrupt these. These aren’t the only ones.

A paper just published in Cell Systems describes screening over 200 proteins from the sera of 31 Covid-19 patients. The research team identified 27 proteins whose relative levels appear to be associated with Covid-19 symptoms, when compared with the sera of healthy donors. These proteins come from a variety of metabolic or immune response processes. Some may be useful in developing better assays for Covid-19, or treatments. Larger scale screening is, however, required.

Covid-19 can trigger nasty physiological cascades

The effects that SARS-CoV-2 can have on the body are still being discovered. An article in The Economist provides a readable overview, as well as highlighting longer-term social and economic impacts that may occur for some who have been severely affected. 

Recent research is finding that, in addition to disrupting a balanced immune response to infection, the virus may damage blood vessels. This can lead to a cascade of organ and tissue damage in those who already have weaker vascular systems.

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