A genetic basis for why some people develop severe forms of COVID-19

- Research

The IGTP has participated in an international study that for the first time describes how the vulnerability of certain people to developing clinically severe forms of the infection caused by the virus SARS-CoV-2 is influenced by their genetic characteristics. The GCAT-Genomes for Life Project of the IGTP has taken part in the study, which has just been published in the New England Journal of Medicine, with a cohort of 20,000 people whose genetic information is known.

The study shows that two regions of the human genome are associated with the risk of developing respiratory failure when infected with SARS-CoV-2. One of them is located on chromosome three and can affect the expression of genes that favour the entrance of the virus and the generation of a cytokine storm, a severe inflammatory response. The second region is localized on chromosome nine, on the gene that determines the ABO blood group. The data shows that having blood group A is associated with a 50% higher risk of needing respiratory support if infected with the coronavirus. By contrast, having blood group O confers 35% less risk of developing respiratory insufficiency.

The researchers set out to answer the question of why some people are asymptomatic or have  mild symptoms, while others develop severe illness when infected by the SARS-CoV-2 virus, in the shortest time possible. This would allow the identification of risk groups that need special protection and help to design pesonalized treatments. The directors of the participating groups explain, "We have found a strong association between certain genetic variants in chromosomes three and nine and the seriousness of the disease caused by the coronavirus."

Collaboration between hospitals in Spain and Lombardy

At the height of the COVID-19 pandemic in Italy and Spain (March-April 2020) researchers from different hospitals in Spain (Basque Country, Catalonia, Madrid and Andalusia) and the Northern region of Italy, Lombardy (epicentre of the pandemic in Europe), started this collaborative study coordinated by genetecists in Norway and Germany. The aim was to find out, in the shortest time possible if there was a genetic predisposition that increased the risk of severe illness from infection by SARS-CoV-2.

The IGTP has taken part through the GCAT Project. "We have participated in the analysis with data from the GCAT cohort, a populational sample that represents individuals exposed to the infection and about whom we have an extensive description of genetic variability. This has allowed us to validate the impact of these variants at populational level," explains Rafa de Cid, Scientific Director of the project at the IGTP.

In just three weeks blood samples were collected from 1,610 patients with COVID-19 that needed respiratory support (oxygen and mechanical ventilation). DNA was extracted from the samples and sent to the Kiel Laboratorhy in Germany, where they studied nearly 9 million genetic variants. To do this they had a team of expert geneticists and bioinformaticians and the support of a rapid financial donation from Norwegian philanthropists.

The researchers explain that "in less than two months we had all the necessary information to evaluate the results with a control group of 2,025 healthy controls. This way they identfied a higher frequency of 26 genetic variants in patients affected by respiratory insufficiency, compared to the control group of uninfected people. Two of them in particular, located on chromosomes three (rs11385942) and nine (rs657152) showed a powerful association with severithy of the disease.

Original article                                                      

Genome-wide association study in severe Covid-19 with respiratory failure. Ellinghaus et al. New England Journal of Medicine, June 17, 2020, DOI: 10.1056/NEJMoa2020283