Objective
Our objective is to discover novel genetic and structural variation within the HLA region that contributes to the risk of developing T1D. Prior research makes it clear, based on “missing heritability” that important genetic risk factors have yet to be discovered. We will apply a novel long read sequencing and analysis strategy to carefully chosen sample sets from individuals with T1D and controls to reveal previously undiscovered genetic variation that contributes to disease risk.
Background Rationale
Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive T cells. There is clear evidence that, prior clinical diagnosis, individuals who go on to develop T1D have genetic factors that place them at risk. The most prominent source of genetic risk is a large cluster of genes known as the human leukocyte antigen (HLA) region. Despite decades of study, the HLA region remains an untapped source of variation because it structure and features have precluded in-depth analysis. Specifically, the region has a high degree of sequence and structural variation and repetitive sequence elements. In the face of these challenges, carefully designed studies continue to reveal new features of the HLA region that contribute to T1D susceptibility. However, only a long-read sequencing approach has the potential to comprehensively reveal the coding, non-coding, and structural variations that underlie T1D disease susceptibility. Base5 Genomics has a long-read sequencing and assembly approach with an unprecedented ability to identify novel features within the HLA region.
Description of Project
Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive T cells. There is clear evidence that, prior clinical diagnosis, individuals who go on to develop T1D have genetic factors that place them at risk – most notably a large cluster of genes known as the human leukocyte antigen (HLA) region. Combining knowledge of HLA risk with additional risk genes has enabled the development of genetic risk scores to classify different forms of diabetes and identify individuals with elevated risk. Unfortunately, the predictive value of current models is undermined by the fact that identified loci cannot explain all of the observed heritability. Despite decades of study, the HLA region remains an untapped source of variation because specific features of this region make it technically difficult to study. We propose to apply a newly developed long read DNA sequencing and analysis strategy to identify novel genetic features that contribute to T1D risk. This improved understanding of genetic risk that would increase our ability to identify individuals with elevated risk and may implicate new pathways that underlie disease.
Anticipated Outcome
We expect that applying this approach to carefully selected sample sets has the potential to provide novel and important insights about genetic factors that promote the risk of developing T1D. Specifically, we expect to identifying novel susceptibility variants by studying subjects who develop T1D in spite of carrying the most protective HLA genotype. We further expect to discover novel structural variations that alter the regulation and expression of HLA and other immune related genes. The end result of this work will be a great understanding of genetic risk, enabling improved genetic risk scores, and the possible identification of new pathways that underlie disease development.
Relevance to T1D
Genetic risk is a key factor that underlies the eventual development of the self-destructive immune responses that destroy insulin producing beta cells in individuals who develop Type 1 Diabetes. The proposed research would generate knowledge about genetic risk that can be used to develop improved genetic risk scores. A successful outcome would confirm that previously undiscovered variation within the HLA region contributes to disease risk. These genes can be expected to illuminate new pathways that underlie development of the disease. The ultimate goal would be to better predict individuals who are at risk of developing T1D and to facilitate new pathways for disease prevention and treatment.