The world has already experienced three coronavirus attacks in the 21st century, beginning with Sars in 2002, Mers in 2016 and now Covid-19. While the first two have been far less infectious but more lethal with fatality rates of 10% and 34% respectively, the Sars-CoV-2 has proved more infectious, but much less lethal with a case fatality rate (CFR) of 3%. As per the World Health Organization organogram, there is a considerable disparity both in infection numbers and death rates among nations with the highest fatality rates recorded in Europe and the Americas, and the least in Africa and the Indian subcontinent.
India has done exceptionally well by keeping CFR at 1.54%. What is even more remarkable is the observed heterogeneity in disease presentation with most infected people remaining asymptomatic or presenting with mild symptoms. Among those who require hospitalisation, only a small percentage develop critical symptoms and lose the battle. According to the ministry of health statistics, age and underlying co-morbidities account for much of this disparity. But could a person’s DNA profile determine the course of Covid-19?
To define the possible role of genetics, experts employ the highly sophisticated techniques of molecular biology to scan the DNA of a set of patients and an equal number of healthy controls (usually upwards of 1,000 each), and look for any informative markers from among millions of DNA sequences and ascertain if any of these confer susceptibility and/or protection from the disease.
The first such study published in the New England Journal of Medicine in June identified two genes linked to respiratory failure in a sample of 1,980 Covid-19 patients with severe disease from Italy and Spain. Of these, one gene located on chromosome 9 coinciding with the ABO blood groups identified higher risk of disease among persons with blood group A and a protective effect for those with blood group O. Similar results were obtained by the Danish health registry indicating least vulnerability of blood group O to Covid-19, as well as a Vancouver study reporting that A and AB blood group types were at a comparatively higher risk of severe symptoms. However, it would be premature to draw any definitive conclusions from these results unless extensive studies are carried out in other populations and the underlying mechanisms get clarified.
The Covid-19 Host Genetics Initiative, an international study group of eminent geneticists, has released a new dataset to suggest that a region on chromosome 3 shows significant association with severe Covid-19 with an odds ratio for requiring hospitalisation to be 1.6. The gene encodes for a protein that seemingly influences interaction between two important cells of the immune system, namely the dendritic cells and T-cells, and thus may directly control the clinical course of the disease. This has been confirmed in a genome-wide association study led by Kenneth Baillie of the University of Edinburgh on over 2,000 critically ill Covid-19 patients suggesting at least half a dozen additional gene variants. These results, if proven by others through appropriately-designed clinical trials, could guide treatment schedules.
Of the additional genes linked to severe Covid-19 in the Edinburgh study is the IFNAR2 that codes for interferon, which acts as a powerful messenger that influences the development of innate and the adaptive immune responses against viral infections. The increased expression of this gene could reduce the odds of severe Covid-19. This raises hopes of better outcomes for ongoing trials of interferons as a plausible Covid-19 treatment. The other five genes act in pairs and influence two biological mechanisms: One set determines innate immunity-driven antiviral defences early in the disease and the other, inflammatory lung injury that occurs later in the disease course and is life-threatening. Again, these claims must be tested in large-scale clinical trials.
In the most comprehensive trans-ancestry sequencing study of Covid-19 involving over half a million individuals, researchers at the Regeneron Genetics Center in New York have focused on three main components namely, susceptibility to Sars-CoV-2 infection, disease severity as determined by hospitalisation and the third of patients who required ventilation or had passed away.
This attempt confirms the involvement of chromosome 3 gene but not the ABO blood groups suggesting that it may be a false positive. Further, they identified three additional novel genes expressed on, one, chromosome 1 and found mostly in individuals of African ancestry, two, chromosome 16 and, three, chromosome 22, the last of which also influences the IFNAR2 gene.
Elucidating host genetics of Covid-19 holds the potential for understanding both susceptibility to Sars-CoV-2 infection as well as heterogeneity in clinical presentation and severity in disease outcome. Genetics could help to explain why most people infected by the virus never feel sick, while others develop serious symptoms and lose their lives.
Dr Narinder Kumar Mehra is Indian Council of Medical Research Emeritus Scientist (Hon) and former Dean of the All India Institute of Medical Sciences, New Delhi
The views expressed are personal