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.

Researchers from Khalifa University have been investigating the specific genome variants that may point to risk factors for certain diseases and seeking to understand how these genetic variations can help develop more personalized treatment plans.

Read Arabic story here: 

Researchers from Khalifa University have recently published a number of articles investigating the nuances of the Emirati genome, following their research published last year describing the sequence of the first complete Emirati genome. They have since been investigating the specific genome variants that may point to risk factors for certain diseases and seeking to understand how these genetic variations can help develop more personalized treatment plans.

Much of the team’s attention has been focused on the genetic risk factors for metabolic syndrome, in particular type 2 diabetes. The discovery and mapping of the complete human genome in 2003 introduced the possibility of individualizing medicine to a person’s physical and genetic makeup, with plans for more population-specific genomic analyses to gain context-specific insights. Evidence is now increasingly suggesting that a patient’s unique genetic profile can be used to detect the onset of a disease and possibly even prevent it.

Dr. Habiba Alsafar, Director of KU’s Biotechnology Center and Associate Professor of Genetics and Molecular Biology, has been studying the unique genomic variants in the UAE population that are associated with diabetes, hypertension, increased cholesterol levels and obesity. Metabolic syndrome is a cluster of conditions occurring together, increasing risk of heart disease, stroke and type 2 diabetes.

The UAE has a high prevalence of metabolic syndrome, which may be linked to genetic risk factors in the local population. However, the association between metabolic syndrome as a phenotype and key genetic variants in the UAE has not been investigated in depth until now.

Dr. Alsafar and her team found clear links between metabolic syndrome and specific genetic and metabolic risk factors, providing an insight into possible causes of disease development. Several gene variants were found to be associated with a predisposition to developing metabolic syndrome, providing clues for disease mechanisms.

“In one study, we found that patients with metabolic syndrome had higher rates of type 2 diabetes, hypertension and dyslipidaemia, a medical condition that refers to abnormal levels of lipids in the blood,” explained Dr. Alsafar. “We noticed that waist circumference and type 2 diabetes were key risk factors for metabolic syndrome and that individuals who developed metabolic syndrome had a higher rate of clinical complications.”

Diabetes mellitus is a group of metabolic diseases, all of which are characterized by high blood glucose levels. It is a major public health problem, particularly type 2 diabetes, which is commonly associated with obesity. Diabetes tends to run in families with genetic factors contributing to its development.

The UAE has a high prevalence of diabetes, consistently ranking among the top five most affected countries in the world. Recent genome-wide association studies have identified more than 400 locations on particular chromosomes that are associated with susceptibility to type 2 diabetes disease. In-depth examination of the Emirati genome in particular could help pinpoint the exact genes that could be contributing to this prevalence.

In another study, the team found that genetic variants of one particular gene, known as TCF7L2, were associated with an increased susceptibility to type 2 diabetes, especially in Emirati males.

“Knowledge of specific risk markers in a population, including at risk genotypes, will help identify individuals who are more likely to develop metabolic syndrome. The ability to do so early, even prior  to development of symptoms, could mean we can delay or even prevent its onset,” explained Dr. Alsafar.

The population in the UAE is also particularly prone to coronary artery disease.  Previous studies having shown strong genetic associations between heart disease and type 2 diabetes. A further study by the team examined the genomes of a cohort from the Arab population of the UAE to replicate previously reported significant genetic associations. The study aimed to investigate how these genes are associated with twelve cardio-metabolic traits that may influence the development of the two diseases. The team did replicate these results, adding significant credence to the research, and also noted that some genes are associated with these diseases regardless of ethnic background. They also detected new links between the diseases with height and with blood type.

Knowledge of an individual’s susceptibility to a disease improves diagnosis and means more informed decisions can be made for a patient’s treatment, potentially helping them avoid metabolic syndrome altogether.  

Through these projects, Dr. Alsafar and her team are contributing to the global body of information and research on how to use context-specific genomic information to advance the understanding of medical conditions, improve treatment and promote healthy lifestyle habits. 

Jade Sterling
Science Writer
18 November 2020

The post Diving into the Emirati Genome to Determine the Genes Associated with Metabolic Syndrome appeared first on Khalifa University.