A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes

Over 100,000 Canadians and 380,000 in the UK overall have type 1 diabetes. People with type 1 diabetes require lifelong insulin injections to replace insulin synthesized by specialized cells in their pancreas that have died due to an immune process. Currently there are few treatments to prevent or delay the underlying destruction of insulin producing cells. However recent studies have shown that many people with type 1 diabetes do in fact still produce small amounts of insulin. This is important because these people have less severe diabetes: they require lower doses of insulin; have better control of their blood sugar levels; are at lower risk for the development of low blood sugar; and also importantly at lower risk for long-term complications of diabetes, including eye, kidney and heart diseases which are major health problems. However, we have little understanding of the factors that result in differences in insulin production capacity between people with type 1 diabetes. Genetics provides a unique opportunity to identify causal factors for important biomedical measures, such as varying insulin production in people with type 1 diabetes. We already conducted a pilot study where we identified genetic variations different locations in the genome that are related to insulin production and have shown that residual insulin production is very strongly genetically determined. However we showed that only a small percentage of the genetic contribution is from known genes so that there are important genes still to discover. Furthermore we showed that age at onset of diabetes is one determinant of residual insulin production but that the genes determining age at onset only capture a small percentage of the genetic determination of residual insulin production.
In this project we will use data and samples from ten different studies, with a total of ~12,200 people with type 1 diabetes, to allow us to identify the genetic factors that influence residual insulin production, age at onset and also glycaemic control separating those genes that influence these traits together from those that have specific effects on each trait. It is important to bring the collaboration together in order to maximise the size of the study to make it as powerful as possible and also to ensure standardised approach as that also increases the power for discovery. This would be the largest and most comprehensive study of this topic to date.
Identifying the genetic factors is the first step to understanding the mechanisms, which could ultimately be used to develop new approaches to help preserve insulin production in people with type 1 diabetes. The work will also lead to ways to identify which people with diabetes are most appropriate participants for which clinical trials which will accelerate drug development programmes. Since insulin production is also abnormal in many people with type 2 diabetes, which affects over 2 million Canadians and over 4 million in the UK overall, the discoveries about pancreatic cell function that we will make will also lead to important insights and accelerate development of new treatments for some people with type 2 diabetes.

The aim of this collaborative project is to understand the genes and pathways underlying variation in residual beta-cell function as measured by C-peptide levels, age at diabetes onset and glycaemic control in type 1 diabetes (T1D). The purpose is to i) yield insights into the biology of beta-cell function, that will inform the development of new therapies to prevent or reverse T1D, ii) to enable stratification of those with diabetes with respect to predicted rate of C-peptide loss iii) to quantify the likely clinical impact of restoring beta cell function or of changing glycaemic control to a given level.
This collaboration will bring together leading researchers from Scotland and Canada; They will combine data from 12,200 people with T1D. The key steps will be: 1) To establish a common analysis plan for conducting genome-wide association studies (GWAS) of these inter-related phenotypes of C-peptide levels, age at onset and HbA1c trajectories. 2)To bring together the cohort specific GWAS results in a meta-analysis thus i)validating previous genotype-phenotype associations for these phenotypes ii)discovering new loci for these traits through a meta-analysis iii) enabling the construction of locus specific and genome wide genotypic scores 3)To use the genotype data in each cohort to compute locus-specific and genome-wide genotypic predictor scores for a range of other phenotypes of interest for which summary GWAS associations statistics are publicly available.4)To use the SNP associations and the genotypic scores to gain greater insight into biological pathways of relevance to beta cell biology and of the causal role of residual beta cell function in complications a number of approaches. 5)These SNP associations and genotypic scores will also be used to i) construct predictive models for C-peptide trajectories ii) quantify the likely impact of restoring beta cell function, or changing glycaemic control, on diabetic complications.

The purpose of the proposed research is to identify the genetic determinants of some key characteristics that vary between people with a clinical diagnosis of type 1 diabetes. These characteristics to the extent of control of day-to-day blood glucose. Up until now, it has been considered that this has been largely reflecting the day-to-day clinical management of disease. We are now realising that there are inherent including genetic determinates of this control. The aspect of the research that we are trying to understand is why it is that some people with type 1 diabetes continue to have some preserved function of their pancreatic cells whilst others do not. We have already established that this is a strongly genetically determined, in part, trait and we will try to understand the genetic determinants of this here and what pathways those genetic determinants operate through. Accordingly, the key impact of our research will be on, first of all, a primary understanding of the mechanisms through which glycaemic control occurs in diabetes and through which the preservation of pancreatic function occurs. If we can understand the pathways leading to these traits then that leaves open the possibility of informing design of new molecules for intervening on these pathways, i.e. new drug development.
The long term impact of our work should be to contribute towards the development of therapeutics that may help to preserve pancreatic function in people with type 1 diabetes or to reverse its loss or even to prevent its loss in the first place.
Impacts of our work should be on the scientific community in a greater understanding of the pathogenesis of type 1 diabetes. Secondly, on the drug development industry in contributing important data on pathways enabling and fostering new molecule identification. Thirdly, on clinical understanding of variation in the clinical course of diabetes so that, for example, it may be possible to consider that some people with a heavy genetic load predisposing them to more brittle type of diabetes would have more intensive management. Fourthly, clinical trialists who might choose to use genotypic information for oversampling the most as risk persons into clinical trials and for estimating likely downstream benefits on complications of modifying beta cell function or glycaemic control. . Finally, and most importantly, the community of people with diabetes itself who will benefit from understanding that there are important genetic factors that they cannot control that may mean that they have less easy or more easy to control diabetes. People with diabetes should also benefit if and when therapeutics are developed that help to modulate the course of their disease that would be informed by the research described here. Of importance is that our understanding of both type 1 and type 2 diabetes should be progressed by this research so people with either type of diabetes may benefit.