Messenger RNA analysis of genes implicated in susceptibility to type 2 diabetes.

We are now facing an epidemic of type 2 diabetes (T2D). This disease, which used to be found only in the middle aged, is increasingly now being seen in much younger people because of rising levels of obesity, lack of exercise and other risk factors. We are beginning to understand, however, why some people are more likely to get T2D, whilst others do not. Everybody's genes are slightly different. We all carry large numbers of very small changes in our genes and some of these changes may make people carrying them slightly more susceptible to diabetes or other diseases. Over the past decade, we have found over 40 changes that make people more likely to become diabetic. We now face an important task to find out exactly how these changes cause diabetes. Most of the changes identified have been in regions of the genes that control whether genes are switched on or switched off. All cells contain all the genes, but not all are switched on in every cell type. When a gene is switched on, it produces a message, which tells the cell to make a particular protein, which may be necessary in the control of blood sugar, or in other bodily processes. Most genes can also make more than one type of message. The amount or nature of these messages is important to keep our cells healthy and to make our bodies function. These small changes in the genes could cause genes to be switched off when they should be switched on, or vice versa. They could also cause the genes to make the wrong sort of messages, or the right messages but at the wrong time. All of these possibilities could contribute to the development of diabetes. In this study, I aim to find out whether the changes in the genes that are associated with T2D affect the amount or number of messages made, and how this could then predispose to diabetes.

Type 2 diabetes (T2D) is a growing public health issue, which places an increasing burden on scarce healthcare resources. In the past decade, we have seen enormous advances in our understanding of the genetics of T2D, with over 40 DNA genetic variants showing an association with susceptiblility to this disorder according to genome wide association studies (GWAS). A major challenge now lies in identifying the causal locus in each case, and determining their mechanisms of action. The vast majority of the observed genetic variation associated with T2D lies in non coding regions of the genome. Although these non-translated regions of the genome produce no proteins, there is a growing body of evidence to suggest that they are far from non-functional. In this study, I aim to determine whether variants identified in the GWAS can influence mRNA processing, mRNA stability or post-transcriptional regulation of the genes in question. I will first carry out a detailed bioinformatic analysis to identify genetic variants within candidate genes which have the potential to differentially affect features of RNA processing or RNA stability. Once promising targets have been identified, I will assess the potential of GWAS variants to affect aspects of mRNA processing or stability in a series of human pancreatic islet and peripheral blood lymphocyte samples. The proposed project is likely to provide mechanistic links between genetic variation and increased risk of T2D. This will aid our understanding of this common disorder and may highlight new pathways for therapeutic intervention.

The work will have impact for the wider academic community in that it will provide an explanation for the associations between the associations seen between genetic variation and susceptibility to type 2 diabetes. This will allow focusing of deep re-sequencing approaches and future in vitro work, showcasing the UK as a major power in scientific innovation. Results will also have impact on clinicians and patients, in that it may yield a clearer understanding of how inherited risk factors can interact with specific genotypes to alter susceptibility to, or progression of disease. Identification of novel coding regions by this study may indicate further regions for genetic screening of candidate loci such as the HNF1A, HNF4A and HNF1B genes, which are also associated with monogenic diabetes. Breakthroughs arising from this study may indicate new therapeutic strategies, or suggest beneficial lifestyle options which will give clinicians a better understanding of how best to manage patients and patients an idea of what they can do to help themselves. The work may also have implications for the wider public sector. A clearer understanding of the basic mechanisms will suggest new disease pathways, and perhaps indicate new therapeutic strategies. This will provide opportunities for the development of new drugs. Modification to messenger RNA splicing patterns by small molecules is already in clinical trials for several disorders (such as Duchenne Muscular Dystrophy), as recently reported in the Lancet. This indicates that the identification of disease-related splicing modifications may prove a particularly fruitful avenue for investigation. This will in turn attract R&D investment from the pharmaceutical industry and increase the profile of the UK in diabetes therapeutics. This may also yield implications for public health in that it may generate markers that are predictive of the onset or progression of type 2 diabetes. This would allow better allocation of resources and more effective screening. Finally, the work will provide a training platform for junior staff to learn skills in public outreach and presentation of complex ideas to lay audiences. It will enable staff to learn skills for critical appraisal of evidence, presentations and public speaking, which will be of use in other arenas.

The timescale to impact in the clinical or industrial setting is by necessity long term for basic science advances, but training advances and benefits to the scientific community will be on a shorter timescale.