Khalifa University’s Dr. Habiba Alsafar and a collaborative team of UAE researchers have identified eight host-specific genetic factors with a ‘highly plausible’ genetic association with hospitalized cases of Covid-19. The findings may be able to help researchers discover therapeutic approaches to combatting the virus responsible for an enormous health and economic burden worldwide.
One of the great mysteries of the Covid-19 pandemic was why some people only contracted a mild disease, but for others it was a fatal infection. The variation in consequences range from asymptomatic to life-threatening, viral pneumonia and acute respiratory distress syndrome. Although some factors correlating to disease severity have been established, these risk factors alone do not explain all of the variability seen.
A research team in the UAE has found that the genetic makeup of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors affect the chance of exposure to the SARS-CoV-2 virus, host genetics seem to play a significant role in the severity of the disease. The research team involved consisted of Dr. Habiba AlSafar, Associate Professor and Director of the KU Center for Biotechnology (BTC), with Dr. Mira Mousa, and Research Associates Hema Vurivi and Hussein Kannout, all from the BTC. They collaborated with a team from Sheikh Khalifa Medical City, Dubai Health Authority, and the University of Western Australia and the work has been published in The Lancet.
In a cross-sectional study, the research team looked at 646 patients who contracted Covid-19, 482 of whom were hospitalized with acute respiratory distress syndrome, pneumonia, severe complications, or who needed supplemental oxygen therapy. Upon examination of their genetic information, they identified eight genes expressed in the lungs are very likely to be associated with hospitalization in Covid-19 cases.
Risk factors, disease management and access to health systems do contribute to the wide variety in Covid-19 symptoms seen but multiple genome-wide association studies have demonstrated a link between the patient’s genetic makeup and their vulnerability to severe Covid-19 infection.
Previous work by Dr. AlSafar with researchers in the UAE found that infection with Covid-19 can affect the expression of various genes known to be associated with inflammatory and oxidation activities in the body. Genes that caused the production of reactive oxygen species – a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell – were significantly upregulated, while genes that affected antioxidant production – molecules that fight free radicals in the body – were downregulated.
Now, a further eight genes have been discovered with a ‘highly plausible’ genetic association with hospitalization cases of Covid-19, thanks to the first genome-wide association study (GWAS) in the United Arab Emirates.
“Identifying genetic variants associated with Covid-19 severity may uncover novel biological insights into diseases pathogenesis and identify mechanistic targets for therapeutic and vaccine development,” Dr. AlSafar explained. “We can identify which individuals may have a greater risk of being hospitalized and improved treatments to target these patients specifically.”
The team designed their approach to uncover genetic variants shared across ancestry groups, discovering that while the eight genes were largely driven by effects in the populations with European ancestry, the effects were similar in multiple ancestral populations, demonstrating the chances of those variants modulating the risk of infection and severity in different populations.
The eight genes were all found in the lungs and are associated with tumor progression, emphysema and airway obstruction within the lung. In hospitalized Covid-19 patients, these genes were associated with respiratory failure that required invasive mechanical ventilation. Some of the genes were also found to be associated with inflammation in the lungs, further validating previous work that indicated inflammatory responses in the lungs influence Covid-19 susceptibility and severity.
While further studies are needed to fully establish the roles these eight genes play, these findings suggest that genetic diversity may be an important factor in determining why different people have different lung responses to SARS-CoV-2, and thus differing severity of Covid-19. Some of these associations could lead to therapeutic approaches, or therapies designed to improve overall health rather than merely treat symptoms, due to their expression in the lungs.
“The sample size for this study was small so caution should be exercised in translating the findings into genetic tests and clinical application,” Dr. AlSafar added. “However, based on our study, one gene, VWA8, has a 3-fold risk of being associated to hospitalized Covid-19 phenotypes. This gene is linked to types of emphysema and deformities in the lungs.
“We need to conduct further studies on worldwide population genetics to see if we can identify these genes in other populations. Then, we can begin to develop population-specific therapeutics to mitigate this worldwide challenge.”
24 January 2022