Establish a network of patient registries and biobanks on Addison’s disease in Europe (WP1) in the involved research centres providing clinical information which describes the epidemiology and natural course of the disease (WP2) in order to overcome the current limitation of published studies which are without exception based on knowledge drawn from insufficiently sized patient cohorts. Hence the intended European-wide network of patient registries will be of a sufficient critical mass of patients for the research purposes outlined in this application. The detailed objectives are to:
- Organise current registries according to the common consortium form.
- Collect serum/plasma, DNA, RNA and in some instances blood cells from the patients.
- Merge the individual registries into a network of registries so that information can be shared among partners.
In recognition of the recent sequencing of the dog genome and the spontaneous high incidence of AAD in certain dog breeds such as the standard poodle and Portuguese water dog, we will identify genes associated with AAD in the dog, and use this information to find the relevant genes in humans and mice (WP3) (dog – human – mouse crosstalk). The detailed objectives are to:
- Collect dogs with AAD and healthy controls from the same breed.
- Perform genome wide single nucleotide polymorphism (SNP) analysis.
- Identify the canine genes associated with AAD.
- Identify and characterise orthologues of these candidate genes in humans and mice (WP3-5).
Identify human genes associated with AAD (WP5). Detection of allelic variants of genes conferring increased disease susceptibility in conjunction with immunological markers of autoimmune adrenalitis (e.g. autoantibodies against 21-hydroxylase) will be used to identify persons at risk of developing AAD. The detailed objectives are to:
- Seek polymorphisms and mutations in genes already known or suspected to be associated with AAD and other organ-specific autoimmune diseases exploiting the power provided by a large patient registry.
- Perform a genome association analysis to identify alleles associated with disease in close interaction with similar analyses in dog (WP3).
- Perform targeted sequencing of leukocyte cDNA to identify rare variants of candidate genes suspected to confer disease susceptibility using novel high-throughput sequencing technologies.
Identify the mechanism(s) and kinetics operational in the immune-mediated destruction of the adrenal cortex (WP4 & 6). We will exploit recent advances in tetramer technology, use our understanding of cell-mediated autoimmunity in related/corresponding autoimmune diseases and employ our know-how to develop gene targeting directed to thymus epithelial cells to generate a novel mouse model of AAD. The detailed objectives are to:
- Identify disease-relevant T cell epitopes in 21-hydroxylase using tetramer technology (WP6).
- Identify the pathogenic events in T cell mediated destruction of the adrenal cortex in a novel mouse model (WP4).
- Study pathogenic T and regulatory T cells in patient samples and in the mouse model of AAD (WP4 & 6).
- Identify patients at risk of developing AAD by autoantibody screening (WP6).
- In order to reduce treatment-related mortality and morbidity, we will develop physiological and personalised steroid replacement (WP7) by implementing a treatment-sensitive quality of life instrument to monitor therapy, and provide European treatment guidelines and patient information. The detailed objectives are to:
- Implement a novel treatment sensitive quality of life questionnaire (ADDIQoL).
- Study new ways to administer cortisol, i.e. slow-release preparation (in collaboration with a SME, see Appendix) and a continuous infusion system.