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.

Research to Support Accurate Classification of Genome Variants for Development of Preventative Healthcare System

A team of scientists from Khalifa University of Science and Technology has completed a significant local genome study that will contribute to nationwide efforts to build a high-quality, comprehensive reference genome for the UAE population.

The first phase of the study — the description of the first whole genome sequences of UAE nationals — was completed in 2019. Subsequently, in 2020, the researchers completed the second phase which described the nature of the genetic diversity found among UAE nationals. This year, the researchers completed the third phase of the UAE reference genome, which supports a broader understanding of the genome composition of the nation.

Following advancements in DNA sequencing and analysis techniques since renowned scientist Craig Venter and his colleagues published the first whole human genome sequence at the turn of this century, the genome study has become part of a major area of research at Khalifa University.

The Khalifa University scientists recently published a report titled ‘A population-specific Major Allele Reference Genome from the United Arab Emirates population’ in the international journal, Frontiers in Genetics. The study was authored by Dr. Habiba Alsafar, Associate Professor, Department of Genetics and Molecular Biology, Dr. Andreas Henschel, Associate Professor, Electrical Engineering and Computer Science, with Dr. Gihan Daw Elbait and Dr. Guan Tay, from the Center for Biotechnology.

Dr. Arif Sultan Al Hammadi, Executive Vice-President, Khalifa University, said: “Our researchers have published the first whole genome of a UAE national and have followed it up with this reference genome.  This will advance our understanding of the genomes of the UAE population, improving the ability of researchers and clinicians to identify genetic causes of diseases that are common in the UAE and the region. This is a stellar achievement in the field of medicine and healthcare, as this will become a fundamental tool that will advance genome and public health research in the UAE, and contribute to nationwide efforts, being led by the recently formed UAE Genomics Council to incorporate genomics into the healthcare ecosystem of the UAE.” 

The ethnic composition of the population of a nation contributes to its genetic uniqueness.  Consequently, it is important to define national reference genomes of its people to avoid any confounding effects which are linked to the use of reference genomes from other national genome sequencing efforts. A total of 1,028 UAE nationals were recruited for this study, as part of the 1,000 UAE genome project that was conceived by the research team when the Center of Biotechnology was founded in 2015. Of these, 129 samples were selected as individuals that are most representative of the genetic diversity of the UAE for construction of the UAERG.

“Despite achieving this major milestone in a relatively short period of time, our work to improve our understanding of how genes contribute to health continues,” said Dr. Alsafar and added, “Our next challenge is to decode the genome data to identify genetic markers that better predict the likelihood of disease.”

Precision medicine has the potential to profoundly improve the practice of medicine. The goal is to enable clinicians to quickly, efficiently and accurately predict the most appropriate course of action for a patient; a pre-emptive strike to prevent or delay the onset of disease.  However, the practice of precision medicine and personalized healthcare is a complex science as it is influenced by a range of factors such as the environment and the inherent characteristics within an individual. Genetics is an important contributor to this complexity and genome science will play a key role in the rollout of future national health programs.

Since the establishment of the Center for Biotechnology (BTC), its primary mission sought to address a gap in knowledge relating to the specific genomic features of the UAE population.  In 2018, the BTC team outlined a vision for a National Arab Genome project for the UAE in the Journal of Human Genetics. The aim was to address the deficiency in genome data on the UAE population to improve our understanding of genome variants that are unique to the population of the nation.  The team led by eminent geneticist Dr. Alsafar, proceeded with the bold ambition to sequence Emirati nationals to provide a reference upon which clinical decisions can be made.

In 2019, Dr. Alsafar led the team that described the first Whole Genomes Sequences (WGS) of two UAE nationals in Nature Publishing Group’s Scientific Report.  “It was important to achieve this milestone, as the whole genome sequences provided a starting point for construction of a UAE reference panel which will lead to improvements in the delivery of precision medicine, which we hope will eventually lead to improvements in the quality of life of UAE nationals” said Dr Alsafar.

Despite reporting on the first genome of a UAE national, the Khalifa University team continued to sequence samples provided by UAE nationals for research. In mid-2020, the team followed up the report of the first UAE Whole Genome Sequence with two papers in Frontiers in Genetics. These studies showed that the contemporary population of the UAE arose from gradual admixture through complex and long term interactions between local communities of the area that is now the UAE and the people of neighbouring regions.

The seven emirates that formed the UAE in 1971 were once sheikhdoms that were homes of communities that existed for centuries. These communities lived on the southern routes of human migration within the Arabian Peninsula. Some of the inhabitants of the region encountered people who led a nomadic lifestyle, travelling widely into and out of neighbouring African, Asian and European states. As these nomadic communities passed through this region, traces of genetic impressions of the populations that they encountered in their travels were left behind.

As researchers continue to probe the secrets entwined in the genome of the UAE population, the construction of this reference genome is intended to drive the developing paradigm that is precision medicine, specifically clinical practice that embraces prevention rather than treating disease once it has taken hold.

Clarence Michael
English Editor Specialist
5 July 2021

The post Khalifa University Researchers Complete Reference Genome Study for the UAE appeared first on Khalifa University.

Many populations in the Middle East are unified by common cultural practices, religion, and language. However, there are differences in the genome sequence within and between these groups.

In a research first, a team of investigators from Khalifa University led by Dr. Habiba AlSafar, Director of KU’s Center for Biotechnology and Associate Professor of Genetics and Molecular Biology, has published introducing the whole genome sequences of two UAE nationals. The study found that unique genome variants exist within the UAE population.

In 2003, the complete human genome was sequenced for the first time and with that breakthrough came an instrumental shift in our understanding of genomics and genetics. Decoding genetic information has led to a greater understanding of human biology, disease susceptibility and drug response to medication, among others. This research constitutes a significant landmark in local biomedical research.

The Human Genome Project originally aimed to map the nucleotides, the building blocks of DNA, contained in a single chromosome set of a human reference genome. Mapping the “human genome” involved sequencing a small number of individuals and then assembling these together for a complete sequence for each chromosome. The finished human genome sequence is therefore a mosaic of several individuals because each human genome is unique. It nonetheless offers a representative example of the human species’ DNA.

Whole genome sequencing (WGS), meanwhile, is the process of determining the complete DNA sequence of a single organism’s genome and provides information on genetic relationships, origin, and susceptibility to specific diseases. WGS has largely been used as a research tool so far but in the future, whole genome sequence data may be an important tool in personalizing therapeutic intervention. If clinicians have access to the information gleaned from sequencing an individual’s genome, they will be able to more accurately predict disease susceptibility and drug response, which will lead to improved health outcomes for individuals and populations.

“Whole Genome Sequencing provides an in-depth description of genome variation,” explained Dr. AlSafar. “In the era of large-scale population genome projects, the assembly of ethnic-specific genomes combined with mapping human reference genomes of underrepresented populations has improved the understanding of human diversity and disease associations.”

Research indicates that members of particular populations are more predisposed to certain hereditary diseases or conditions than others. Among Emiratis, common genetic and non-communicable diseases include obesity and diabetes, but until recently, Middle Eastern populations comprised just one percent of the genome data in the public domain.

“There is an intolerable gap in the human genome landscape,” said Dr. AlSafar. “Despite the best efforts of the Human Genome Organization and other international consortia, genome data from ethnic groups of the Arab-speaking world is substantially underrepresented.”

Since the completion of the first human genome, DNA sequencing technology has progressed substantially. This Next Generation Sequencing (NGS) technology is now faster and less costly. Using NGS technology, the team at Khalifa University took the first steps to rectifying this.

Of the approximately 10 million people living in the UAE, only about 10 percent are national citizens. Their genome has been greatly influenced by the transcontinental migration of myriad different ethnic groups and the nomadic lifestyles of the Arabian populations originating from the region, particularly the Bedouins.

“The Middle East sits at the crossroads of significant human migration between the African, European and Asian continents,” added Dr. AlSafar. “The eventual development of trade routes further increased bi-directional gene flow through the region, creating the contemporary diversity seen in modern Arabia.”

Interpreting ethnolinguistic differences, geopolitical relations and cultural diversity can only produce so much understanding of the origins of the Emirati population. The need for concrete genetic data motivated the sequencing of the WGS for two Emirati citizens. These sequences now contribute not only to the national understanding of local citizens, but also to the bank of data about middle-eastern populations, including the four WGS from the Kuwait genome project, and 104 WGS from Qatar.

The two citizens were both 87 years old, one male and one female. The male sample was analyzed using Principle Component Analysis (PCA) and supervised biogeographical ancestry analysis (or admixture analysis) in which all populations from the Human Genome Diversity Project Database were used as possible ancestral populations.

“The extent of variability in the two Emirati genomes was determined by comparison to genomes from different world populations,” explained Dr. AlSafar. “This adds credence to the likelihood that the various populations that now inhabit the southeastern tip of the Arabian Peninsula were created by the migration and population movement common throughout the region spanning from Southern Asia across the Levantine region and the Arabian Peninsula to North Africa.”

The sequencing may have been motivated by a desire to better understand population diversity and ancestral origins, but this data has wide-reaching health benefits as well.

Before their genomes were sequenced, the disease status of each participant was known. Both had hypertension among other complications.

“Variants that have previously been shown to be associated with diabetes, hypertension, increased cholesterol levels, and obesity were identified in the genomes of these individuals,” explained Dr. Alsafar. “Disease susceptibility and many inherited traits are affected by interactions between different variants located in multiple genes spread across the genome. It is important to note that these genetic variations alone do not provide definitive diagnosis of a specific disorder.”

Rather, the presence of a genetic variation offers insight to an individual’s likelihood of developing a condition. Knowledge of an individual’s susceptibility improves diagnosis and means more informed decisions can be made for a patient’s treatment. The patient’s genetic information can be used to determine optimal doses of treatment and the likely therapeutic response to certain medications which can help reduce or even eliminate any adverse side effects and contribute to reducing waste and the cost of healthcare in the UAE.

Plus, a more in-depth appreciation of how genes affect a person’s response to drugs among UAE and Arab patients can lead to new drug development, says Dr. AlSafar: “The information compiled will likely lead to the identification of target genes that could potentially lead to the development of novel therapeutic modalities.”

“More importantly, as healthcare moves from one that is based on treating the isease to one based on preventing its occurrence in the first place, genome data will become invaluable.”

In many parts of the world, the cost of treating disease is expected to become prohibitive as the population ages. A sensible means of managing the increasing cost of healthcare is through precise, preventative intervention using personalized genome information. Prevention has the added benefit of ensuring a better quality of life for the individual, a healthier society and a more productive local economy.

The study is also an example of cross-institutional cooperation between researchers and clinicians. Biomedical science is a fledgling discipline in the UAE. Nevertheless, as competencies in molecular research and bioinformatics in the country grows, a collaborative approach will only accelerate the process of future discoveries. It is therefore essential that the biomedical fraternity comes together for the sake of contributing towards a healthier nation.

Jade Sterling
News and Features Writer
31 October 2019

The post The First Whole Genomes of Nationals from the United Arab Emirates Emerge from Khalifa University appeared first on Khalifa University.