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.

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.”

Jade Sterling
Science Writer
24 January 2022

The post Eight Genes Found to Influence Covid-19 Severity appeared first on Khalifa University.

Two patients with unique genetic mutations in a single gene sparked the investigation of 40 researchers into the effects of gene expression on diabetes 

The discovery and mapping of the complete human genome in 2003 introduced the possibility of individualized medicine to a person’s physical and genetic makeup. Increasing evidence is now demonstrating that a patient’s unique genetic profile can be used to detect a disease’s onset, prevent its progression, and optimize its treatment.

This has led to enhanced global efforts to implement precision (personalized) medicine and pharmacogenomics in clinical practice. One such area of clinical practice is the treatment of diabetes.

In contrast, the most common types of diabetes are caused by multiple genes or lifestyle factors. Most cases of monogenic diabetes are inherited.

Dr. Pierre Zalloua, Professor and Chair of the Department of Molecular Biology and Genetics, collaborated with researchers from France, Germany, Austria, the United States, and Singapore to determine the gene responsible for two cases of monogenic diabetes. Their results were published in.

“Diabetes affects over 350 million people worldwide, and the discovery and study of genes responsible provide important insights for understanding disease mechanisms,” Dr. Zalloua explained. “With better understanding, we can improve quality of life and develop cost-effective care for diabetes patients.”

Diabetes mellitus is a group of metabolic diseases, all of which are characterized by high blood glucose levels. If left untreated, diabetes can lead to severe complications including blindness, kidney and heart disease, stroke, loss of limbs, and reduced life expectancy. It is a major public health problem, affecting hundreds of millions of people worldwide and representing a substantial economic burden on society. 

There are two types of diabetes: Type 1 and Type 2 diabetes. Type 1 usually begins in childhood with individuals suffering from their body’s inability to produce enough insulin, while Type 2 is commonly associated with obesity and usually occurs during middle age. Both types tend to run in families and genetic factors contribute to the disease, with interactions between genetic and environmental factors being critical. 

Dr. Zalloua said. “Remarkably, many of these genes encode key proteins for pancreas development.”

To determine which genes play a part in the development of diabetes, the research team examined two different patients with diabetes: one, a young French boy with neonatal diabetes, and a second Turkish child with diabetes diagnosed at 14 months. They showed that the patients inherited mutated alleles of one particular gene, ONECUT1. Two mutated alleles led to a severe form of neonatal diabetes where the child developed a small pancreas and a missing gall bladder, while one mutated allele saw an increased risk of diabetes in the second patient. The researchers were able to determine that ONECUT1 and its expression is a major player in diabetes.

Dr. Zalloua was the person who originally identified additional cases from the region linked to this gene, including a case from a patient in Lebanon. Analysis of these patients revealed various different ONECUT1 mutations, all linked to a risk of diabetes.

ONECUT1 affects a variety of processes including glucose metabolism, an important factor in the disease mechanism of diabetes. Its expression also influences the development of the pancreas and the gallbladder. Previous studies of ONECUT1 have focused on the gene’s role in retinal development, but it is now clear that ONECUT1 acts to determine what type of cell a stem cell becomes. Some human stem cells are pluripotent, meaning they can become any kind of cell in the body, and genes including ONECUT1 are the deciders. Mutations in this gene can therefore disrupt a very complex process at various stages.

The pancreas plays an essential role in converting food to fuel in the body: it helps in digestion and in regulating blood sugar. Two of the main pancreatic hormones are insulin, which acts to lower blood sugar, and glucagon, which acts to raise blood sugar. A functioning healthy pancreas automatically produces the right amount of insulin; in people with diabetes, the pancreas either produces little or no insulin, or the cells do not respond to the insulin that is produced.

To further validate their findings, the researchers examined a cohort of over 2000 German people with presumed type 2 diabetes, and identified 13 incidences of ONECUT1 mutations. In another, larger and multi-ethnic, cohort of almost 20,000 people with type 2 diabetes, the researchers also found that people with variants of the ONECUT1 gene were more likely to develop type 2 diabetes. However, they noted that the risk varied with the specific variant.

Identifying the cause means we can pinpoint the best treatment, offering an opportunity to shift focus from broad population-based standards of care to tailored treatments targeted to an individual molecular profile.

“We found that ONECUT1 controls mechanisms regulating endocrine development, which is involved in a wide spectrum of diabetes types,” Dr. Zalloua said. “We highlighted the broad contribution of ONECUT1 to diabetes pathogenesis, marking an important step towards precision medicine for diabetes.”

Jade Sterling
Science Writer
18 January 2022

The post Khalifa University Researcher Contributes to the Finding of a Novel Gene Involved in Human Diabetes appeared first on Khalifa University.

The body’s immune system has an incredible mechanism capable of responding to various pathogens, but it can go too far. New research from a team in the UAE has found that Covid-19 infections can affect the way the genes moderating this immune response are expressed, which may be why infections range from asymptomatic to severe.

When the body is confronted with an infection, an immune response is triggered, sending immune cells to the region to attack the virus. This causes localized inflammation that reduces once the body has treated the attack. Sometimes, however, this immune response can go into overdrive, resulting in hyper-inflammation. While this sounds fairly innocuous, this can seriously harm or even kill the person.

This is how contracting the flu can kill a patient. In the context of Covid-19,

Cytokines are small proteins released by many different cells in the body as an immune response and a cytokine storm is an overreaction from the body’s immune system.

Some cytokines trigger cell death to prevent a virus spreading to other cells, but when lots of cells do this, a lot of tissue can die. In Covid-19 patients, that tissue is mostly in the lungs. As the tissue breaks down, the tiny air sacs fill with fluid, causing pneumonia and starving the blood of oxygen. Respiratory distress syndrome follows, other organs start to fail, and the patient dies.

Now, , the biological mechanisms that cause oxidative stress and that are combated by antioxidants. While most well-known for their anti-ageing properties, antioxidants are the components that keep oxidative stress in check during an immune response, and in Covid-19 patients, this balance is disrupted, contributing to the cytokine storm.

Dr. Habiba Alsafar, Associate Professor and Director of the Khalifa University Center for Biotechnology, collaborated with Prof. Rabih Halwani, who is Principal Investigator on the project, along  Prof. Qutayba Hamid, Dr. Narjes Saheb Sharif-Askari, Dr. Fatemah Saheb Sharif-Askari, and Bushra Mdkhana, from Sharjah Institute of Medical Research and College of Medicine, University of Sharjah; Hawra Ali Hussain Alsayed from the Dubai Health Authority Pharmacy Department; and Dr. Zeyad Faoor Alrais from the Dubai Health Authority Anaesthesia and Intensive Care Unit. Their results were published in .

“When patients suffer high levels of oxidative stress while infected with a respiratory disease, their prognosis tends to not be very good,” Dr. Alsafar said. “We know that the virus causing Covid-19 enters the cells by binding to the host ACE2 receptors, and these receptors are found in abundance in the lungs. When this virus infects the cells, there is an extreme drop in ACE2 levels, and this is bad news because ACE2 plays a critical role in regulating the oxidative balance. A lack of ACE2 means the production of reactive oxygen species is stepped up. Moreover, activated inflammatory cells that infiltrate the infected lung tissue produce large amount of these oxygen species. Where a healthy cell would then activate an antioxidant response, this mechanism is suppressed in patients with a severe Covid-19 infection. There is evidence to suggest this is a targeted effect of the Covid-19 virus to enhance its survival in a patient.”

The UAE research team measured the gene expression levels of 125 genes known to be associated with inflammatory and oxidation activities in the body from Covid-19 patients and compared their levels with those seen in influenza (IAV) patients and respiratory syncytial virus (RSV) patients. They also compared the severe Covid-19 infections against non-severe Covid-19 infections.

“We wanted to know how Covid-19 infection may affect the expression of these genes in patients and found that the genes that caused the production of reactive oxygen species were ‘significantly upregulated’ in patients with Covid-19,” Prof. Halwani said. “While the oxidative genes were upregulated, the antioxidant genes were found to be downregulated.”

In severe Covid-19 cases, the antioxidant resources were completely depleted in the infected cells, resulting in a further increase in reactive oxygen species products and a cytokine storm.

“Targeting one or more of these oxidative stress genes could be an effective therapeutic approach for treating Covid-19,” Dr. Alsafar said. “This could help prevent the progression of the disease to a cytokine storm, stopping an over-reactive immune response before it happens. We could also give patients direct doses of antioxidants to help combat the oxidative stress seen in infections.”

“Interestingly, three of the oxidative genes that were significantly upregulated in severe cases could be detected in saliva samples, suggesting that the saliva level of these genes could be used as non-invasive markers for Covid-19 disease severity,” Prof. Halwani said. While further studies are needed to confirm these findings, they represent a significant step towards understanding the Covid-19 disease mechanisms and a possible treatment plan. 

Jade Sterling
Science Writer
28 November 2021

The post Enhanced Oxidative Stress Aggravates Cytokine Storm and Lung Tissue Damage During Covid-19 Infection appeared first on Khalifa University.