Objective
1) Utilize the existing whole-genome sequencing data to identify type 1 diabetes risk genes in the Middle East and North African population represented by the local population of Qatar to develop a genetic risk score to define “at-risk”-individuals of future type 1 diabetes.
2) Taking advantage of available, advanced, scalable, and cost-effective technology, which can be integrated into readily available assay platforms for islet autoantibody testing in clinical laboratories.
Background Rationale
Many diseases that are heritable, allowing us to predict the likelihood of their onset with genetic screening and diagnostics. Type-1 diabetes presents an excellent example of those diseases as host genetics plays a strong role in its development, providing a window for early diagnosis and intervention in the young. This has motivated large-scale studies, involving many known affected and unaffected individuals, to determine the genetic components underlying type-1 diabetes.
In type-1 diabetes, the body’s own immune system attacks the pancreatic cells responsible for insulin production, resulting in pancreatic mass loss, insulin deficiency, and eventually high blood sugar levels. Interestingly, the immune attacks against the pancreas could begin years before the presentation of disease symptoms, and the main perpetrator of the attacks, called “autoantibodies” are used to determine if the attacks on the pancreas have begun. However, screening for autoantibodies can be both difficult to perform in children and costly, creating the need for tests that rely on the unique genetic information of the individual.
A new and effective genetic-risk based test was developed based on the recent analysis of the genetic information from over 15,000 type-1 diabetes and unaffected individuals’ genomes from the Type 1 Diabetes Genetics Consortium. By considering the genetic information from this many individuals, the confidence in the performance of the genetic test becomes higher, ultimately allowing better predication of disease outcome and reducing the overall costs at the clinical front. The newly developed genetic test can also better distinguish between type-1 and type-2 diabetes, allowing physicians to make more accurate diagnoses and providing at-risk children with valuable information to prevent clinical progression of the disease and the most effective treatment course.
The development of this genetic test is a testament to the promise of precision medicine to revolutionize the standard of care. Furthermore, the potential of this genetic test to guide more accurate diagnoses and prevent life-threatening complications of type-1 diabetes are indispensable and unlocking this potential to its fullest could be the first step to stop the progression of type-1 diabetes in its track.
Description of Project
Type 1 diabetes, also know as juvenile diabetes, is an autoimmune disease with a pre-symptomatic stage of variable length. A large percentage of cases onset in childhood, adolescence, and young adulthood, but the disease can develop at any age.
Extended time before a diagnosis can result in affected individuals suffering diabetic ketoacidosis (DKA), a dangerous and on many occasions a fatal condition. Even when DKA at diagnosis does not lead to death, researchers and clinicians now understand that it is associated with long-term destruction for patients. Researchers at the have developed a new method to predict the risk of type 1 diabetes at early stage. The risk score which considers detailed genetic information known to increase the chances of type 1 diabetes. This could be utilized to help identity babies at highest risk of developing the condition in the future. Population screening
Screening for T1D autoantibodies can offer information on risk for future progression to clinical symptoms and prevent DKA at diagnosis. The presence of two or more T1D autoantibodies indicates a very high likelihood of progression to clinical disease. Eighty-five percent of people who develop T1D have no relatives with the disease. Therefore, to identify the majority of people at risk before clinical disease onset, screening cannot be limited to family members. Screening the general population for T1D genetic risk and autoantibodies has multiple benefits. It can recognize people most at risk for progressing to clinical T1D. It can also provide a chance to educate and prepare families for disease symptoms and treatment, resulting in a reduction of DKA presentation at diagnosis. Moreover, therapeutic interventions under clinical development could meaningfully delay the onset of T1D, further validatingthe possible future benefit of T1D screening in the general population.
Anticipated Outcome
The course Type-1 diabetes typically begins much earlier than the presentation of symptoms, with the host’s genetic elements determining susceptibility. The proposed combined approach will target various points of disease course to accurately determine the risk to developing type-1 diabetes. First, we will develop an ‘integrated genetic metric’ that will aim to predict type-1 diabetes development at any point shortly after birth. We will generate this genetic metric based the large-scale, parallel analysis of numerous pre-existing genetic information found in genomes from the Qatar Genome Project. The genetic testing will allow the discovery of genetic markers specific to the pan-Arab population, which we expect to align with current genetic markers specific to T1D in other populations, with potential minor differences. The integrated metric could thus be used as a gold standard in assessing the genetic risk to developing type-1 diabetes, further stratifying the population based on their genetic susceptibility and guiding the decision-making for further invasive testing.
Given the diverse ethnic background and stratified genetic structure of the pan-Arab population, we anticipate that the analysis of genomes from the Qatar Genome Project will yield a robust metric; however, we also recognize that this robust metric will need further performance testing against the current population and using our technology at Sidra Medicine. To this end, the performance and accuracy of the integrated genetic metric will be tested by implementing the analysis on genetic information gathered from individuals outside of the Qatar Genome Project – the group of individuals that form the ‘validation’ cohort. Here, prior knowledge of clinical/family history will be key to recruiting individuals into the validation cohort, and we anticipate that we will complete recruitment and genetic testing for the majority of the type-1 diabetes susceptible population in Qatar, as all patients with family history for T1D are referred to Sidra Medicine.
In type-1 diabetes, the pancreatic cells responsible for insulin production diminish due to the host’s own immune cells’ attack on the pancreas. This occurs through Y-shaped proteins that normally target foreign invaders to the body, but in this case target the body’s own cells. These proteins, called ‘autoantibodies’ usually develop sequentially, and when there are two or more of them, the person becomes more susceptible to developing T1D with time. Yet, in some rare instances, and due to unexplained reasons, type-1 diabetes may develop without the emergence of these known autoantibodies, in a subtype of the disease known as type-1b diabetes which has a strong genetic background. These characteristics necessitate a dual approach to disease detection that rely on both genetic and immunological detection. In our combined approach, we pair the family/medical history-guided genetic testing with an immunological test developed at Sidra medicine to accurately detect the autoantibodies in the bloodstream. Given the small cost of $5 and the ease of performing this assay in terms of accessibility and amount of blood required, we anticipate the rapid and accurate detection of autoantibodies as they emerge.
A major factor of discouragement for patient participation in research is the pain associated with the often-large volume of blood needed for patients to provide to participate in research. By leveraging Sidra Medicine’s genomics and flow-cytometry core services, we will be requiring a tenth of the blood volume usually required in other research facilities in our approach, increasing participants willingness to join our research. The proposed combined approach will provide patients with insights guided by their unique set of genetic information as early as shortly after birth and the ability to monitor type-1 diabetes progression over time from the comfort of their home.
Relevance to T1D
Type-1 diabetes requires many conditions to develop and present symptoms. A complex set of known and unknown genetic elements unique to the host may interact with environmental factors such as diet and exercise to slowly promote disease development and eventually cause the dysregulation of blood sugar level and onset of disease symptoms. Unfortunately, in the initial stages of disease development there no symptoms and the blood sugar levels remain normal, making early-disease prediction inaccurate without robust screening for the disease risk using genetic and immunological methods. This is where AL-DAIR approach comes in, combining the information from the individual’s genetic background and their immunology to guide disease prediction and prevention.
The incidence and prevalence of type-1 diabetes in the Arab world has skyrocketed over the past 20 years, leaving an increasingly heavy burden on the physical and mental health of the communities, and draining large economic resources to manage the persistent disease. The high-income Arab counties such as Saudi Arabia, Kuwait are known to have a high incidence rate of type-1 diabetes, often ranking among the top 10 in terms of incidence in annual reports. In particular, Qatar was recently shown to be the 8th highest in terms of type-1 diabetes occurrence, with increased genetic and serological identification showing higher rates of type-1 diabetes occurrence. This is consistent with an epidemiological shift where Qatar is experiencing less communicable diseases, but more chronic diseases associated with acquiring a western lifestyle and making poor health choices relating to dieting and exercise. Complicating this increasing rates is that half of the patients suffering from type-1 diabetes are unaware of their disease progression and they are at greater risk for further complications associated with diabetes and in turn increased morbidity. Awareness and early testing to determine genetic risk remains key in preventing the progression of disease and has the potential to improve the life quality and expectancy of many patients.
The occurrence rates of type-1 diabetes in the Arab world are driven by special, region-specific, sociocultural aspects. The Arab population is, in general, characterized by a high consanguinity
rate, with increasing rates of divorce over the past decade, both of which are factors that increase the occurrence of the disease. Furthermore, a significant proportion of the Arab population fasts during Ramadan, which is particularly discouraged in type-1 diabetes as it raises the blood acidity level and further worsens the severity of life-threatening complications such as diabetic ketoacidosis. These region-specific factors distinguish the underlying causes of type-1 diabetes in the Arab world and present an opportunity to determine new insights in how the genetic information and the environment may work together to shape type-1 diabetes occurrence in the regional population.