Objective
Our main aim is to use this genetic information to improve the diagnosis of adult-onset type 1 diabetes in the multi-ethnic US population. We will also aim to expand our understanding of the genetic basis of adult-onset type 1 diabetes.
Genetic studies so far have identified many genetic risk factors for type 1 diabetes. However, the use of this information in routine clinical practice is very limited. We will translate these genetic discoveries into clinics. We have developed a simple and inexpensive genetic tool called a type 1 diabetes genetic risk score (T1DGRS). It combines all known genetic risk factors of type 1 diabetes in a single test. This makes it easy to use for research and clinical practice. We will use this new tool to improve the diagnosis of adult-onset type 1 diabetes.
We will conduct our study in a large Geisinger cohort of ~175,000 people. This cohort already has detailed clinical information, blood for lab tests (biomarkers) and in-depth genetic data. We will use this genetic data to for our tool and make sure that this tool works for the multi-ethnic US population.
Our goal is to check how good our new genetic tool is for identifying adult-onset Type 1 diabetes. We will test this tool in >10,000 people with adult-onset diabetes from many ethnicities.
We will check if this new tool improves the diagnosis of type 1 diabetes compared to commonly used tests (islet autoantibodies). We will also check if the new tool improves the diagnosis of type 1 diabetes compared to the clinical information (such as the age of the patient and blood glucose levels) that are commonly used for the diagnosis of type 1 diabetes. We will also check the usefulness of this tool in people from Hispanic and African ancestry who have adult-onset type 1 diabetes in the US.
Our second goal is to improve our understanding of the genetic basis of adult-onset type 1 diabetes. For this we will use an existing database of genetic information from 175,000 participants of Geisinger health system, including >5000 individuals with adult-onset type 1 diabetes. Comparing genetic information between those with type 1 diabetes and people without diabetes will allow us to, for the first time, to search for new type 1 diabetes genetic risk factors in all 20,000 human genes.
This new information will make our tool even better for clinical use. We may also identify new drug targets for type 1 diabetes.
Background Rationale
Half of all type 1 diabetes presents in adult life. Yet much research is focused on childhood-onset type 1 diabetes. Our most knowledge on the biology and genetic risk factors are from studies in childhood-onset type 1 diabetes.
Improving diagnosis
The lack of accurate diagnosis is a major hurdle for adult-onset type 1 diabetes. Nearly half of them are diagnosed as not having type 1 diabetes at the onset. This affects their clinical care and prevents research into adult-onset type 1 diabetes.
Our current tools to diagnose type 1 diabetes are helpful but they have limitations. The presence of Islet autoantibodies suggests type 1 diabetes. But they are absent in up to 30% of adult-onset type 1 diabetes. They also reduce over time. The very low level of insulin in the body also suggests type 1 diabetes. But it is less helpful at the onset as people still make insulin early in their diabetes.
We have developed a new tool that can overcome the limitation of current tests. This tool provides information on the genetic risk of type 1 diabetes in an individual. We call this tool the type 1 diabetes genetic risk score (T1DGRS). It is simple and inexpensive. You can measure it in blood. It uses genetic information from DNA. This means the test result is available from birth and does not change with time.
Our recent studies show that our tool is helpful in diagnosing type 1 diabetes in the UK population. Our preliminary work shows that it performs well in children with type 1 diabetes from the multi-ethnic US population. However, T1DGRS remains to be tested in an adult-onset type 1 diabetes, multi-ethnic US population.
The study population will come from Geisinger, a large integrated health system in Pennsylvania, USA. We will study a multi-ethnic cohort of 175,000 participants, including >5000 with type 1 diabetes, who have already provided samples for research. These samples have been used to generate in-depth genetic data. This genetic data has been linked with detailed clinical information from electronic health records. We also have stored research blood samples from these individuals. We will use this to measure currently used biomarkers of type 1 diabetes. These existing resources makes our study very cost-effective and low risk.
Improving genetic basis
Understanding the genetic basis of type 1 diabetes can help to understand why people develop type 1 diabetes. It can help find drug targets for prevention or treatment. Previous genetic studies were helpful but limited by technologies that could only capture a fraction of genes. New technologies provide comprehensive genetic information on all 20,000 genes in humans. Recently the Geisinger MyCode cohort has made this information available for research. It contains DNA information on 175,000 people. This gives us a unique opportunity to study all human genes together. We will use these available data to find new genetic risk factors for adult-onset type 1 diabetes.
Team
We are a team of researchers with experience in type 1 diabetes and human genetics at Geisinger, US and the University of Exeter, the UK. We have a strong track record of successful research into type 1 diabetes and human genetics. We have a successful ongoing collaboration. We have performed many of the initial clinical studies of our new genetic tool. We have substantial experience in studying large cohorts with genetic and electronic health records. The Geisinger investigators have >10 years’ experience in utilizing Geisinger’s longitudinal electronic health records to develop clinical phenotypes to study disease risk and genetic basis, including genetic risk scores.
Description of Project
Our proposal will use knowledge of the genetic basis of type 1 diabetes to improve type 1 diabetes diagnosis and management.
Our main aim is to use genetic information to improve the diagnosis of adult-onset type 1 diabetes in the multi-ethnic US population. We will also expand our understanding of the genetic basis of adult-onset type 1 diabetes. This will help to find a novel drug target for the treatment and prevention of type 1 diabetes.
Our proposal focuses on adult-onset type 1 diabetes. This represents half of all type 1 diabetes, yet it is the least studied. Most of the knowledge on the biology of diabetes and genetic risk factors are from studies in childhood-onset type 1 diabetes.
The lack of accurate diagnosis is a major hurdle for adult-onset type 1 diabetes. This affects their clinical care and prevents research into adult-onset type 1 diabetes.
Nearly half of all people with adult-onset type 1 diabetes are diagnosed as not having type 1 diabetes at the onset. This problem is much more pronounced for people of non-European ancestry. They are often treated with oral medication when they are first diagnosed. This leads to poor glucose control and the risk of life-threatening complications like ketoacidosis.
We want to improve this situation. We propose to do this by using our new genetic tool. This tool captures the genetic risk of type 1 diabetes. We call this tool the type 1 diabetes genetic risk score (T1DGRS). It is simple and inexpensive.
Our previous studies show that our tool is helpful in the UK population which is mostly from European ancestry. But we do not know if this works in the multi-ethnic US population. To study this, we will use our unique study population from Geisinger Health (Pennsylvania, US). It is a large multi-ethnic cohort of 175,000 people, with >5000 people with adult-onset type 1 diabetes. It has detailed clinical information from electronic health records. It also has stored blood samples for research. Importantly, it has in-depth genetic information for our study.
The genetic data also includes complete information on all 20,000 genes in humans. This will help us find new genetic factors causing type 1 diabetes that have not been possible to study before. This will lead to future refinements of the genetic risk score, as well as important new insights into type 1 diabetes biology that may help treatment and prevention of type 1 diabetes.
Our proposal will change the way we diagnose adult-onset type 1 diabetes in the US. We will produce simple guidelines for researchers and clinicians in the US to use our tool. This will substantially boost research into adult-onset type 1 diabetes and greatly improve their clinical care. We will generate robust data for the regulatory approval of this new tool for widespread use in the US.
Our study will also create a large unique rich resource for the research community. This will boost the much-needed research into under-studied adult-onset type 1 diabetes in the US.
Anticipated Outcome
Our work will provide both short-term and longer-term improvements for adult-onset type 1 diabetes. Our work will also help people from African and Hispanic ancestry who currently have worse health outcomes. We will substantially improve the diagnosis of adult-onset type 1 diabetes, which is a major hurdle for better care and prevents much-needed research into adult-onset type 1 diabetes.
In the short term, this study will:
- Show how best to use T1DGRS genetic tool for diabetes classification in routine clinical practice and research for the multi-ethnic US population.
- Provide detailed data for regulatory approval of this new tool.
- Make T1DGRS freely available for use across the world.
- Demonstrate these tools improve the diagnosis of type 1 diabetes in people from African and Hispanic ethnicity.
- Show how best to combine T1DGRS and currently used tools for diagnosing adult-onset type 1 diabetes for clinical use and for research use.
- Create a freely available web calculator to diagnose adult-onset type 1 diabetes using T1DGRS and current tools.
- Generate clear recommendations for researchers on how to use T1DGRS, biomarkers and electronic health records alone or together to select adult-onset type 1 diabetes for their studies.
In the medium to long term, this study will:
- Identify new genetic risk factors that will improve our ability to better predict who will develop type 1 diabetes in the future.
- Provide novel drug targets for the treatment or prevention of type 1 diabetes.
- Better diagnosis will promote the inclusion of adult-onset type 1 diabetes in therapeutic trials. This will facilitate conducting/recruiting patients for clinical trials. This will also make the results relevant to all individuals with type 1 diabetes rather than the subset of type 1 diabetes.
- Our tools will allow scientists to leverage the existing cohorts to study adult-onset type 1 diabetes. This will boost much-needed research into adult-onset type 1 diabetes and contribute to ongoing efforts headed by JDRF to study type 1 diabetes in the non-European ancestry population.
- Create a large resource with genetics, biomarkers, and clinical data for adult-onset type 1 diabetes. This will boost the clinical research into adult-onset type 1 diabetes in the multi-ethnic US population.
Relevance to T1D
Our proposal is directly relevant for people with type 1 diabetes from multiple ethnicities in the US. Our proposal aims to improve the lives of individuals with adult-onset type 1 diabetes, which represents half of all type 1 diabetes.
There are an estimated 800,000 people with adult-onset type 1 diabetes in the US. Our proposal focuses on these people for which our knowledge is limited. Our proposal is relevant for people of African and Hispanic ancestry where our understanding is even more limited.
We specifically aim to improve the diagnosis and genetic understanding of adult-onset type 1 diabetes. Nearly 40% of individuals with adult-onset type 1 diabetes are misdiagnosed. They are initially treated with oral medications rather than life-saving insulin treatment. The lack of a clear diagnosis is also a huge source of anxiety for people with type 1 diabetes.
We will develop and share simple tools to improve the current situation. These can be used along with the current diagnostic tools to help in routine healthcare. They will also help scientists to study adult-onset type 1 diabetes by better identifying and recruiting in the study. We will make our tools available freely.
The new genetic discovery may lead to newer therapy for the prevention and treatment of type 1 diabetes. This will make our proposal relevant to millions of people with adult-onset type 1 diabetes across the world.