Every individual possesses a nearly identical genetic makeup, with around 99.9% of their DNA code being shared. The remaining 0.1% accounts for the inherent distinctions among people, encompassing their inclination towards inherited ailments. Despite genetic sequencing being a conventional diagnostic examination, it is regrettably intricate to establish if particular minute divergences in our DNA amplify the possibility of contracting a disease. Consequently, the efficacy of DNA sequencing is usually constrained to isolated scenarios where it is already established that a genetic mutation elevates the hazard of disease.
Scientists at the University of Copenhagen's Department of Biology have made a breakthrough in addressing this issue for the GCK gene in particular. Their research findings have been recently released in the scientific journal Genome Biology.
Rasmus Hartmann-Petersen, Professor at the Department of Biology, explains:
The gene GCK encodes for glucokinase, an enzyme that governs insulin secretion in the pancreas. Genetic mutations in GCK can lead to an inherited form of diabetes. While the correlation between GCK and diabetes has been established for some time, only a small percentage of the gene's potential variants and their effects have been identified until now.
The researchers, in collaboration with their colleagues at the PRISM center, UCPH, who are currently researching the impacts of genetic variations, evaluated the impact of every possible variant of GCK.
PhD student Sarah Gersing, who is the first author of the article, explains:
Over 9000 distinct GCK variations were evaluated for their activity using yeast cells. The resultant data enabled the researchers to compile a comprehensive list of effects, including those of previously identified variants as well as unidentified ones that patients may carry. This serves as a reference for future GCK diagnoses.
Prof. Kresten Lindorff-Larsen, who heads the PRISM centre, continues:
The outcomes of this study are quite exceptional, as the researchers not only evaluated the impacts of several thousand variants but were also able to elucidate the mechanism by which many of these variants affect the glucokinase protein. The research team, composed of experts from diverse fields spanning data analysis, biophysics, cell biology, and medicine, exemplifies the effectiveness of a broad approach in understanding the etiology of diseases.
One of the potential consequences of gene variants in GCK is the onset of a hereditary form of diabetes referred to as "GCK maturity onset diabetes of the young" (GCK-MODY).
Dr. med. Torben Hansen, a professor of genetics and a member of the PRISM center, notes that GCK-MODY patients tend to exhibit high blood glucose levels but without the associated complications typical of other types of diabetes. As a result, most GCK-MODY patients might not require medication. However, due to the absence or inaccuracy of genetic data, over half of GCK-MODY patients are misclassified as having either type 1 or type 2 diabetes and thus are unnecessarily treated with medication. The researchers estimate that around 1% of recent type 2 diabetes cases in Denmark may be attributed to a variant in the GCK gene, indicating that these patients do not require medication or may need different treatment. The newly created GCK variant map can aid in providing more accurate diagnoses to these patients.
The next step for PRISM is to transfer these methods to other genes and diseases.
Rasmus Hartmann-Petersen mentions that they have already made substantial progress in identifying genes that contribute to neurodegenerative diseases. The team is currently working on developing precise methodologies that can provide them with insights into the mechanisms underlying these diseases.
Kresten Lindorff-Larsen continues:
The data obtained from this study presents the researchers with an opportunity to test and refine computational models for analyzing the effects of genetic variations. These models can then be applied to other genes and diseases.
Sarah Gersing notes that the team has successfully measured the effects of nearly all variants of GCK and gained knowledge about which variants are functional and which are not. The next step in their research is to understand the underlying molecular mechanisms that lead to a variety of different diseases, despite having the same mechanisms.
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