Prof. Fahd Al Mulla and his colleagues are looking into why certain COVID-19 instances are more severe than others.
The heterogeneity in outcome, which spans from quiet infection in some patients to mortality in others, as well as the 'extended COVID' that some patients experience, has been a remarkable characteristic of COVID-19. This heterogeneity is unsurprising for a novel illness spreading fast through a varied population, but knowing what drives it would be crucial in determining how to deal with the pandemic and limit its effects.
Although older persons, men, and those with underlying medical issues are more likely to have severe COVID-19 infections, these characteristics do not account for the wide range of outcomes. In some individuals, an international team of experts theorized that inborn mutations in immune-related genes may be associated to the development of life-threatening COVID-19. To investigate this theory, they formed the COVID Human Genetic Effort, an international cooperation.
This concept appeals to genomics researcher Fahd Al Mulla of the Dasman Diabetes Institute, who has long believed that illnesses are caused by faulty molecules and molecular pathways. He and his coworkers were enthusiastic to join the consortium when they first heard about it. "Real achievement is achieved via teamwork," he explained. The consortium was eager to provide their knowledge. Al Mulla has spent the last five years working to enhance the condition of genetic data on the Kuwaiti population.
Scientists employ statistical methods to find associations between uncommon variants and the illness they're researching to determine out which of the millions of genetic changes in each human genome could be connected to a condition, such as susceptibility to severe COVID-19. However, the reference data must reflect the diversity of human populations for this to function. The majority of genomics data comes from Europeans, yet variations that are uncommon in those groups may be ubiquitous elsewhere.
Al Mulla has contributed to the worldwide effort to correct this imbalance by sequencing the genomes of Kuwaitis. He has acquired genetic data from healthy Kuwaitis and Kuwaitis with chronic health disorders using a mix of microarrays and high-throughput sequencing, and the genome sequences are coupled with well-characterized medical histories.
He has explored the genetics of cancer and diabetes in the Kuwaiti population using these technologies, assessing how effectively results from other countries can be applied locally. He stated, "We need to explore the variance in different populations." "We need to investigate and understand how to apply genomic medicine not only in the US, Arab, or Chinese populations, but in all of them, and to accomplish so, we need a database that captures all of the diversity," says the researcher. When searching for variances in the response to global disorders like COVID-19, diversity in genetic data is extremely essential.
Data from 659 patients with life-threatening COVID-19 from Asia, Europe, Latin America, and the Middle East were evaluated by the team. The researchers intended to see if COVID-19-related life-threatening pneumonia was connected to mutations in three immunological genes previously linked to life-threatening influenza pneumonia. They also identified 10 additional loci that are linked to the three core genes and have previously been associated to other viral infections.
The scientists discovered 118 genetic variations that were more prevalent in individuals with severe COVID-19 by comparing their genomes to those of 534 persons with mild or asymptomatic COVID-19. Experiments revealed that the majority had no influence on the gene's function, but 24 had a negative impact. The researchers concluded that abnormalities in these genes make a person more likely to acquire a severe case of COVID-19 if they become infected since these variations were found in eight of the thirteen loci investigated.
By comparing the genomes of 534 people with moderate or asymptomatic COVID-19 to those of those with severe COVID-19, the researchers revealed 118 genetic changes that were more common in people with severe COVID-19. Experiments found that the majority of the genes had no effect on gene function, but 24 had a negative effect. Because these variants were discovered in eight of the thirteen loci studied, the researchers concluded that defects in these genes make a person more likely to have a severe case of COVID-19 if they become infected.
Similar outcomes were discovered in cells with a mutation in another gene, INAR1. Changes in INAR1 exclusively influence type I interferons, whereas IRF7 is linked to both type I and type III interferons. During the acute phase of COVID-19, the researchers examined type I interferon levels in the blood of their patients and discovered that 10 of them had extremely low levels. Overall, our findings suggest that type I interferons play a key role in the response to COVID-19. "What we discovered is that many cases of severe COVID-19—people dying from the disease—are caused by variations in the interferon genes, which result in ineffective interferons," Al Mulla explained.
As a result, providing type I interferons to some COVID-19 patients might be a beneficial treatment approach. Al Mulla is also interested in non-genetic variables that influence COVID-19 results. Al Mulla has been researching the relationship between fasting blood glucose levels and COVID-19 severity with the help of Hamad Ali, a colleague at the Dasman Diabetes Institute. In general, hyperglycemic individuals are more susceptible to infections and complications, and diabetes is linked to a higher risk of severe COVID-19.
Blood glucose has been used in studies of the relationship between the two as a discrete variable (such as high or low depending on a threshold) or as a linear variable. Both methods are imprecise approximations that might hide crucial information. When glucose levels above the threshold, the former makes a significant shift, whereas the latter regards all increases in blood glucose levels equally.
The current study catches subtleties that were missing by previous techniques by fitting a smoothly changing curve to the connection between blood glucose levels and ICU admission from COVID-19. They discovered that even a minor rise in fasting blood glucose within the normal range was linked to a significant increase in the probability of ICU admission in COVID-19 patients. "This difference is clinically significant, and it highlights the need of closely monitoring glucose levels upon admission," Ali added.
The researchers anticipated that when glucose levels rise, the mechanism connecting glucose levels to COVID-19 outcomes shifts from energy metabolism impacting viral replication at low glucose levels to chronic inflammation impairing the immune response at higher glucose levels. Al Mulla and Ali, along with Mohamed Abu-farha and Thamer Alessa, have begun a clinical investigation of the insulin sensitizer pioglitazone as a therapy for moderate or severe COVID-19 based on these findings. "This is tremendous progress in our fight against COVID-19," Al Mulla said, adding that he is excited to see more individuals participate in the experiment. We're saving people's lives."
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