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Interpreting genetic variants in type 2 diabetes

Numerous genetic variants in the human genome have been linked to type 2 diabetes. However, as most of these variants do not lie within protein coding genes, it is not yet known how they contribute to disease. Now, researchers from Massachusetts General Hospital have developed an online resource to help uncover the impact of these genetic variants on type 2 diabetes.

Type 2 diabetes

Diabetes is a complex metabolic disease, characterised by elevated blood glucose levels. In total, the condition affects around 463 million people worldwide. Type 2 diabetes (T2D) accounts for almost 85% of diabetes cases. This type of diabetes is strongly related to age, obesity and a sedentary lifestyle. Epidemiologic studies suggest that there is likely to be a 25% increase in global prevalence of T2D by 2030. This makes the study of diabetes a top research and healthcare priority.

Genetic variants in type 2 diabetes

Progressive pancreatic islet dysfunction is  thought to cause themajority of cases of diabetes. Understanding this dysfunction is therefore key to gain insights into disease pathology.

Great efforts have been made to try to uncover the link between genetic variants and complex disease susceptibility. In T2D, around 700 genetic loci have been identified to date. The vast majority of variants in these loci do not affect protein sequences. Therefore, the mechanisms by which these variants influence predisposition to disease remains unknown.

Moreover, as the number of newly identified risk variants keeps increasing, their functional interpretation remains an important bottleneck to gain insights into the underlying molecular mechanisms of disease. Interpretation of these variants is also preventing the development of more effective and targeted preventive and therapeutic strategies.

A database to interpret genetic variants in type 2 diabetes

This study, published in Cell Reports, relies on the knowledge that abnormalities in islet cells in the pancreas drive the development of T2D. However, it is very difficult to obtain samples of human islet cells, so there is a lack of available data. To overcome this, researchers from Spain, Belgium, Italy, Sweden, Finland, the UK and the US have come together to obtain more than 500 human islet samples from patients with and without T2D. The scientists then extracted genomic and gene expression data from these samples.

Using this data, researchers from Massachusetts General Hospital created TIGER (Translational human pancreatic Islet Genotype tissue-Expression Resource). Overall, the TIGER portal integrates the newly generated data with T2D genomic and genetic resources to facilitate the translation of genetic signals into their functional and molecular mechanisms. Formation of this resource was made possible using supercomputing re-sources and new statistical methods.

Analysis of TIGER has revealed that certain genetic variants in islet cells from patients with T2D control the expression of particular genes. So far, 32 novel genes were identified that may contribute to type 2 diabetes risk.

Summary and future implications

In summary, this study generated a large expression regulatory variation resource in human pancreatic islets. The results are available through the publicly available and accessible TIGER web portal, which is basically a user-friendly visualisation tool for exploring the datasets, democratising human islet genomic information to all researchers and clinicians.

‘This resource will be very useful to identify genes that may be related with the genetic variants that we have found associated with type 2 diabetes,’ says co-senior author Josep M. Mercader. ‘Knowing the gene behind a given genetic association is the first step for identifying potential drug targets, or to better understand the physiology of different types of diabetes.’

Image credit: xb100 – FreePik

More on these topics

Diabetes / Genetic Variants / Treatment