COVID-19: Behind the scenes geneticsDecember 5, 2020
Recently, four drugs being used experimentally for the treatment of COVID-19 have been disapproved by World Health Organization, declaring them to be ineffective. This declaration created a controversy as it was based on a mega-clinical trial called Solidarity Trial, conducted and organised by WHO in about 30 countries. However, claims have now cropped up that the so-called ‘ineffectiveness’ of the drugs was largely due to underlying genetic reasons related to the participants. The pharmaceutical companies which manufacture these drugs had raised such concerns, buthad failed to generate much interest or backing from the medical community, perhaps because it was WHO which had disapproved the drugs. Now, a paper published in Nature Genomic Medicine states that it was individual differences in terms of pharmacogenomics that made the drugs fail. Simply put, the reason for the failure of the drugs lies in how the genes and the molecular mechanisms of individual patients affected the drugs’ ability to defeat the ‘deathly hallow’- the COVID-causing coronavirus.
According to Pamala Jacobson, author of the above study, the application of pharmacogenomics can help to eliminate fatal hypersensitivity of COVID-patients towards certain drugs like hydroxychloroquine prescribed for the disease. She suggests that an examination of the individual’s genetic information before selecting the medication and dosage for COVID-19 treatment could improve the effectiveness and safety of the drug. The researchers thoroughly reviewed the details about all the drugs used for COVID-19 treatment, including hydroxychloroquine, remdesivir, tocilizumab and steroids. They could identify a number of genetic markers that can improve the efficacy and safety of these drugs. The authors of the paper, Pamala Jacobson and Melanie Nicol — faculty members at University of Minnesota College of Pharmacy — feel that genetic studies in patients with COVID-19 are needed before the routine testing of drugs and involvement in the clinical trials can be recommended. The findings published in Nature Genomic Medicine can be summarised as follows:
There are several gene variants that alter how the body of an individual patient metabolizes and processes the drug molecule prescribed for COVID-19 treatment. This can increase the risk of adverse effects.
Adverse effects may be very complex in nature, as COVID-patients may be taking other medications and may hav a history of other illnesses that can affect the drug.
Data for pharmacogenomics on COVID-19 is limited as the investigations relating to the treatments and clinical trials still haven’t passed preliminary stages.
DNA Polymorphism and COVID-19
COVID-19 is strangely and tragically selective. There is a dramatic rise in the morbidity and mortality due to COVID-19 with age and individual health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive nature of disease, though it is often observed in a small, but significant, proportion of infected individuals. The reason behind this ‘phenomenon’ remained largely unknown. The SARS-CoV-2 infection depends on two host cell factors. They are: (1) Angiotensin-Converting Enzyme-2 (ACE-2) and (2) Trans-Membrane Serine Protease (TMPRSS-2). ACE-2 helps with the entry of the virus into the host cells and TMPRSS-2 enables protein priming for the spike proteins of the SARS-CoV-2. ACE-2 is encoded on the X-chromosome and it catalyzes the conversion of angiotensin II to angiotensin. Angiotensin is a vasodilator and exerts important modulatory effects on the cardiovascular system. TMPRSS-2 is a key gene in the development of prostate cancer. Recent genetic research has proved that the expression of both ACE-2 and TMPRSS-2 are likely to dictate SARS-CoV-2 tissue tropism. In a recent paper published in BMC Medicine, researchers have reported unique genetic susceptibility across different populations in ACE-2 and TMPRSS-2.
Specifically, ACE-2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions. This was observed in African/African-American populations. Unique but prevalent polymorphisms offer potential explanations for differential genetic susceptibility to COVID-19. They may be acting in combination with other risk factors such as cancer and the higher risk profile of male patients.
The authors of the BMC paper further suggest that polymorphisms in ACE-2 and TMPRSS-2 could help and guide physicians worldwide to identify effective treatment options using drugs like hydroxychloroquine and camostat for COVID-19. Clinical studies have reported that incidence and mortality rates are significantly different between male and female COVID-19 patients. These studies also proved that the severity of COVID-19 is associated with pre-existing conditions, such as cancer and cardiovascular disorders. It can be more detrimental in patients with hypertension receiving anti-hypertensive medications. Therefore, researchers propose a systematic investigation of the functional polymorphisms in ACE-2 and TMPRSS-2 among different human populations, such as, African/African-American, Latino/Admixed American, Jewish, East Asian, Finnish, Non-Finnish European, South Asian, etc. They believe that it could pave the way for precisely formulated personalized medicine and genetics-based treatment strategies for COVID-19. Systematic identification of host genetic pathways and DNA polymorphisms can modulate the risk of infection and severe illness, including the over-exuberant immune response to the virus that makes the patient’s condition worse.
Genetics of Interferon and COVID-19
What makes individual responses to COVID-19 drugs so different in their efficacy from person to person? Researchers from University of Paris, Rockefeller University and Howard Hughes Medical Institute in New York, in collaboration with some other teams across the world, have answered this key question for the first time. They found that some patients have a defect in the activity of type-I interferons, the molecules of the immune system that normally act against any kind of viral activity. The researchers propose that their discoveries would make it possible to detect people who are at a high risk of sustaining serious repercussions from COVID-19. The results of the study, published in the journal Science, describe genetic abnormalities in patients with severe forms of COVID-19. All the events that happen at a molecular level are concerned with around 13 genes which govern the type-I interferon-controlled immune response against the influenza virus. Mutations in these genes can cause the production of defective type-I interferon which can lead to severe forms of influenza. Surprisingly, these genetic variants are also
present in adults who have not previously been particularly ill with influenza.
Regardless of age, people with these mutations in their genes governing the type-I interferon are at a greater risk of developing a potentially fatal form of influenza or COVID-19. But there is a quick and simple way to detect these high-risk groups of patients: By conducting a ‘Serum IFN type-I Assay’ using the ultra-sensitive digital ELISA technique. The earlier the test is conducted, the better will be the therapeutic prospects of the patient. In the second study, also published in Science, researchers stated that they could identify a high level of antibodies in the blood of patients with severe forms of COVID-19. The higher amount of autoantibodies produced by type-I interferon are capable of neutralizing the effect of the anti- COVID-drug molecules. These researchers found that the autoantibodies are found in more than 10% of the patients developing severe pneumonia due to a SARS-CoV2- infection. However, they are absent in people who develop a mild form of the disease, and are also rare in the general population. These kinds of patients could benefit from plasmapheresis (removal of the liquid portion of the blood containing white blood cells and antibodies), and other treatments that may reduce the production of these antibodies by B-lymphocytes. So, the need for a genetic base for the treatment of COVID-19 is not only obvious, but also imperative.
COVID Human Genetic Effort
Even at the time of the onset of the COVID-19 pandemic, researcher Jean-Laurent Casanova and his team set up an international consortium, COVID Human Genetic Effort, to identify the genetic and immunological factors that could explain the occurrence of severe forms of the disease by focusing on patients with the severe forms. By targeting their research on a specific mechanism of immunity – the type-I interferon (IFN) pathway, the researchers could highlight genetic abnormalities in certain patients that reduced the production of the type-I interferon (3-4% of severe forms). In other patients, they identified that it was the history and prevalence of autoimmune diseases that blocked the action of type-I interferon (10-11% of severe forms). All these discoveries would thus explain severe forms of COVID-19, which covered about 15% of the total patient population. The analysis of a control sample of 1,227 healthy people also facilitated an evaluation of the prevalence of auto-antibodies against type-I interferon at 0.33% in the general population, a prevalence 15 times lower than that observed in patients with severe forms. These results suggest that the general population should be screened for these antibodies and it can have a huge benefit in the treatment regime.
The Franco-American laboratory of Jean-Laurent Casanova and Laurent Abel has already identified a hundred genetic diseases that may explain susceptibility to infections. While some people recover more or less easily from infections such as herpes, influenza, tuberculosis and hepatitis A, others develop serious clinical forms that can even be fatal. This is because they carry an alteration in a gene involved in the immune response to infection. In view of their knowledge of other pathologies and the discoveries already made on COVID-19, the researchers decided to determine whether errors in the genetic machinery altering the production of the type-I interferon can be repaired. In the course of their research, they also learned that type-I interferon (IFN type-1) can also serve as one of the markers of the response to infection. IFN type-1 normally produced rapidly following any viral infection, but is deficient as a response to SARS-CoV-2. In addition, the viral load in the blood was very high, indicative of the poor control of viral replication by the immune system. This created a ‘runaway’ pathological inflammatory response in the body of the patient, eventually leading to fatal influenza pneumonia or other viral infections, which can make the SARS-CoV-2 infection more severe.
With the help of the COVID Human Genetic Effort Consortium, the laboratory of Jean-Laurent Casanova and Laurent Abel tried to determine the effects of TLR3 and IRF7 genes which are involved in the production of type-I interferon. A total of 13 genes — whose mutations were found to be playing a crucial role in severe SARS-CoV-2 infections — were screened in 656 patients. The patients belonged to various origins, aged from one month to 99 years, and were hospitalized for severe pneumonia due to SARS-CoV-2. Among these 656 patients, a total of about 117 variants were identified. However, only 1 variation was found in the 534 patients with asymptomatic or mild forms. After experimentally testing these variants, the researchers concluded that there are about 8 genes, TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1 and IFNAR2, which can have a deleterious effect in COVID-19 patients. For the other gene-variations, they could not observe any effect on the immune response relating to SARS-CoV-2 infection. The researchers found that 101 of the 987 patients with SARS-CoV2 infection had high levels of neutralizing autoantibodies. At the same time, no neutralizing autoantibodies were detected in asymptomatic or in those with mild forms of COVID-19.
The GEN-COVID Project
For the first time, Italian scientists have been able to identify the genetic and molecular basis for this susceptibility to infection as well as the possibility of contracting a more severe form of the disease. The research was presented to the 53rd Annual Conference of the European Society of Human Genetics, held online from 6 to 9 June 2020. Professor Alessandra Renieri, Director of the Medical Genetics Unit at University Hospital of Siena, Italy, wanted her team’s GEN-COVID Project to collect genomic samples from COVID-patients across the whole of Italy to identify the genetic basis for the high level of clinical variability of symptoms. Using whole exome sequencing of 130 COVID- patients from Siena and other Tuscan institutions, they were able to uncover a number of common susceptibility genes that were linked to a favourable or unfavourable outcome of infection. The researchers will now analyse a further 2,000 samples from other Italian regions, specifically from 35 Italian hospitals belonging to the GEN-COVID project. These results will have significant implications for health and healthcare policy. Understanding the genetic profile of patients may allow the ‘repurposing’ of existing medicines for specific therapeutic approaches against COVID-19 as well as speeding the development of new antiviral drugs. The research could also lead to the development of a ‘COVID Biobank’ accessible to academic and industry partners.