Final Report Summary - GENETICS OF T1D (Using gene to phenotype studies to identify type 1 diabetes genes and their functions)
Type 1 diabetes is one of the most common chronic diseases in children. Currently there are no treatment options for this disease and patients are subject to a life-long insulin replacement therapy to prevent the clinical complications associated with this disease. Importantly, the incidence of the disease has been rising rapidly during past decades and it is predicted to double in children under the age of 5 within the next 10 years. To reverse this trend, it is therefore urgent to identify better diagnostic markers, predictive of early disease events, to identify high-risk individuals, at a stage where they more likely to respond to therapy or preventive primary care.
The causes for the increase in the incidence of type 1 diabetes are still unknown, largely because we still have an incomplete knowledge of the biological mechanisms that underlie the pathogenesis of the disease. In the last few years, large-scale genome-wide association studies have contributed dramatically to our current understanding of the genes involved in the etiology of type 1 diabetes. The major challenge that we now face is to translate this genetic data into a functional setting, to understand the molecular mechanisms that underlie the etiology of type 1 diabetes.
The systematic gene to phenotype approach applied in this study have provided new evidence for the putative role of three independent and genetically-validated biological pathways in the pathophysiology of type 1 diabetes. These results have led the publication of a peer-reviewed manuscript reporting not only the novel association of a genetic variant in the IL-6R gene with type 1 diabetes, but also further elucidating the functional effect of this polymorphism on IL-6 signalling and how it mediates disease protection. Importantly these results could have a clinical application in the stratification of patients for upcoming clinical trials targeting the IL-6 signalling pathway and could inform the design and dosing regimen of such trials to maximise their efficacy and reduce potential safety concerns associated with drug administration.
In addition, we also anticipate that the results stemming from the other two projects will lead to the publication of peer-reviewed manuscripts and will provide important insight into the role of the interferon pathway and the peripheral immunoregulation, in particular of the B- and T-cell compartments, in type 1 diabetic patients. These data will provide functional evidence to support the genetic data and further our understanding of the genetic basis of type 1 diabetes. Another benefit from the ongoing collaborations that have been set up will be a better communication between the genetics and the clinical community. There is a need to understand the inherent heterogeneity of the clinical manifestations associated with type 1 diabetes, and the use of a genetic approach could be very beneficial to understand that heterogeneity and design effective and well powered clinical trials. Conversely, our close collaborations with the clinical and immunology communities will be important to improve future studies on the mechanism of disease, by providing access to large and well phenotyped patient samples that are critical for the design of these studies.
Technically, the generation of large genome-wide gene expression datasets will be a valuable resource to the development of novel analytical methods. These studies will take advantage of the latest generation of microarrays providing a deep coverage of the entire genome, and will represent the most comprehensive analysis of the transcriptional profile of type 1 diabetes patients to date. The improving statistical, phenotyping and bioinformatic tools will be critical to reveal the biological networks that underlie common multifactorial diseases. An important outcome could be the characterization of an inherited phenotype indicative of an early disease mechanism that could be assayed robustly. There is an urgent demand for readouts and phenotypic markers in ongoing clinical trials in type 1 diabetes and in other autoimmune diseases. In type 1 diabetes, the current biomarkers are autoantibodies and C-peptide levels but markers that precede these established, but downstream, markers are necessary to underpin trials that include mechanistic studies.
A second major implication from these genetic studies is that they allow developing better primary prevention of type 1 diabetes. This knowledge of the biological pathways that contribute to disease pathogenesis will accelerate the understanding of their interaction with the environmental factors that can act as co-factors in the development of anti-beta cell autoimmunity. Identification of higher risk individuals at an early phase could contribute to effective preventive approaches and lifestyle changes to reduce the risk of developing the disease.
The causes for the increase in the incidence of type 1 diabetes are still unknown, largely because we still have an incomplete knowledge of the biological mechanisms that underlie the pathogenesis of the disease. In the last few years, large-scale genome-wide association studies have contributed dramatically to our current understanding of the genes involved in the etiology of type 1 diabetes. The major challenge that we now face is to translate this genetic data into a functional setting, to understand the molecular mechanisms that underlie the etiology of type 1 diabetes.
The systematic gene to phenotype approach applied in this study have provided new evidence for the putative role of three independent and genetically-validated biological pathways in the pathophysiology of type 1 diabetes. These results have led the publication of a peer-reviewed manuscript reporting not only the novel association of a genetic variant in the IL-6R gene with type 1 diabetes, but also further elucidating the functional effect of this polymorphism on IL-6 signalling and how it mediates disease protection. Importantly these results could have a clinical application in the stratification of patients for upcoming clinical trials targeting the IL-6 signalling pathway and could inform the design and dosing regimen of such trials to maximise their efficacy and reduce potential safety concerns associated with drug administration.
In addition, we also anticipate that the results stemming from the other two projects will lead to the publication of peer-reviewed manuscripts and will provide important insight into the role of the interferon pathway and the peripheral immunoregulation, in particular of the B- and T-cell compartments, in type 1 diabetic patients. These data will provide functional evidence to support the genetic data and further our understanding of the genetic basis of type 1 diabetes. Another benefit from the ongoing collaborations that have been set up will be a better communication between the genetics and the clinical community. There is a need to understand the inherent heterogeneity of the clinical manifestations associated with type 1 diabetes, and the use of a genetic approach could be very beneficial to understand that heterogeneity and design effective and well powered clinical trials. Conversely, our close collaborations with the clinical and immunology communities will be important to improve future studies on the mechanism of disease, by providing access to large and well phenotyped patient samples that are critical for the design of these studies.
Technically, the generation of large genome-wide gene expression datasets will be a valuable resource to the development of novel analytical methods. These studies will take advantage of the latest generation of microarrays providing a deep coverage of the entire genome, and will represent the most comprehensive analysis of the transcriptional profile of type 1 diabetes patients to date. The improving statistical, phenotyping and bioinformatic tools will be critical to reveal the biological networks that underlie common multifactorial diseases. An important outcome could be the characterization of an inherited phenotype indicative of an early disease mechanism that could be assayed robustly. There is an urgent demand for readouts and phenotypic markers in ongoing clinical trials in type 1 diabetes and in other autoimmune diseases. In type 1 diabetes, the current biomarkers are autoantibodies and C-peptide levels but markers that precede these established, but downstream, markers are necessary to underpin trials that include mechanistic studies.
A second major implication from these genetic studies is that they allow developing better primary prevention of type 1 diabetes. This knowledge of the biological pathways that contribute to disease pathogenesis will accelerate the understanding of their interaction with the environmental factors that can act as co-factors in the development of anti-beta cell autoimmunity. Identification of higher risk individuals at an early phase could contribute to effective preventive approaches and lifestyle changes to reduce the risk of developing the disease.