JDRF UK Centre for Diabetes Genes, Autoimmunity, and Prevention (D-GAP)


Director: Professor Mark Peakman


Objective

The goal of this Center is to establish direct causal relationships between T1D-associated gene polymorphisms and immunological phenotypes. The genetic profile of an individual determines whether he or she runs the risk of developing T1D. Of the T1D susceptibility genes identified, many by investigators in this Center, most, if not all, operate within the immune system, making it likely that T1D results from a failure of the regulation of immunity to self. Likewise, measurements of islet-specific immunity in the blood, again identified or elaborated by key personnel in our Center, are becoming recognizable as defining features of T1D. At least some of the blood immunophenotypes are likely, at some level, to be causative in T1D, although this is more challenging to prove directly because of the unknown effects of disease on their manifestation. As an a priori hypothesis, we propose that some of the T1D genes directly affect some of the immune phenotypes we study. By confirming this link we would identify causative immune phenotypes in T1D, which could become the legitimate targets of drug development and surrogate markers for measurement in prevention and intervention trials. We believe that robust gene-phenotype aetiological links of this type have not been made to date as a result of several factors; very few studies have attempted direct genotype:phenotype linking experiments; they have been carried out on small numbers; they have used T1D patients in whom the phenotypes may be unreliable or exaggerated as a result of disease.

Goals and Aims of D-GAP

We aim to develop a dedicated programme of work, in which adequately powered studies are carried out on carefully genotyped populations, selected for the extremes of protection versus susceptibility for single gene polymorphisms. As well as studying patients with T1D, we will also characterize the same associations in populations without overt disease, to avoid unknown modifying effects of diabetes. Study groups will include first-degree relatives (FDRs) of T1D patients, themselves at defined low and high risk for disease, as well as healthy non-diabetic subjects with the same genetic background. This approach is the nearest one can aspire to in terms of mirroring the analysis of in-bred rodent strains, the classical, direct means for analyzing genotype-phenotype interactions. To undertake such a body of work requires the bringing together of the constellation of efforts and talents that are currently active in UK T1D research, with expertise in population- based studies; unrivalled genotype analysis; and internationally recognized expertise in human islet autoimmunity. Between 2008 and 2013 the UK will also benefit from the fertile environment for such studies generated as a result of the Diabetes Research Network, created by government and covering a population of over 20 million. As we undergo transition to translation, we propose a research programme that will coalesce with ongoing UK T1D clinical networks and the new government-sponsored healthcare framework in the UK as part of an essential “next step” towards T1D prevention studies. As a first step towards this, D-GAP members are driving forward a series of Phase 1 studies of peptide immunotherapy in T1D funded by JDRF in partnership with the Australian Diabetes Vaccine Development Center.

Project 1: Associating T1D genes and CD4 T cell islet autoreactivity

Project 2: Functional analysis of novel HLA class I risk genes in T1D

Project 4: Immune phenotypes and T1D genes

Core A: Clinical Cohorts: collection of first degree relatives, T1D patients and healthy control subjects

Core B: Genotyping, databasing and statistics

Core C: Autoantibodies