A new risk factor
Rare genetic mutations lead to increased risk of type 2 diabetes
It is believed that type 2 diabetes is partly caused by inherited genetic factors, but many of the genes are still unknown. Previous large-scale studies have depended on effective "matrix genotyping" techniques to measure genetic variation across the genome. This approach is usually good at catching common genetic differences between people, although individually each of them gives only a small increase in the risk of diabetes.
Recent technological advances have made it possible to carry out larger-scale genetic measurements by reading the complete DNA sequences of more than 20,000 genes encoding proteins in humans. Proteins are important molecules that allow our body to function. In particular, this new approach made it possible for the first time to conduct a large-scale approach to studying the effects of rare genetic variants on several diseases, including type 2 diabetes.
After examining data from more than 200,000 adults in the UK Biobank, researchers from the Epidemiology department of the Medical Research Council (MRC) of the University of Cambridge used this approach to identify genetic variants associated with the loss of the Y chromosome. This is a well-known biomarker of biological aging, which is observed in a small part of circulating white blood cells in men and indicates a weakening of the body's cell repair systems. This biomarker has previously been linked to age-related diseases such as type 2 diabetes and cancer.
In the results published in Nature Communications (Zhao et al., GIGYF1 loss of function is associated with clonal mosaicism and inverse metabolic health), the researchers identified rare variants of the GIGYF1 gene that significantly increase susceptibility to Y-chromosome loss, as well as a six-fold increase in individual risk of type 2 diabetes. In contrast, common variants associated with type 2 diabetes cause a much more moderate increase in risk, usually much lower than twofold.
Approximately 1 in 3,000 people carries such a genetic variant of GIGYF1. The risk of developing type 2 diabetes is about 30% compared to 5% in the general population. In addition, people who were carriers of these variants had other signs of broader aging, including weaker muscle strength and more body fat.
GIGYF1 is thought to control the signaling of insulin and cell growth factor. The researchers say their findings identify GIGYF1 as a potential target for future research to understand the common links between metabolic and cellular aging and inform future treatments.
"Reading human DNA is a powerful way to identify genetic variants that increase the risk of developing certain diseases. For complex diseases such as type 2 diabetes, many options play a role, but often only increase our risk by a tiny amount. This particular option, although rare, has a big impact on individual risk," he said. Dr. John Perry of the MRC Epidemiology Department and senior author of the paper.
Professor Nick Wareham, Director of the MRC Epidemiology Department adds:
"Our results highlight the exciting scientific potential of sequencing the genomes of a very large number of people. We are confident that this approach will bring a new rich era of informative genetic discoveries that will help us better understand common diseases such as type 2 diabetes. Now we will be able to offer more effective ways to treat or even prevent this condition."
Current research will focus on understanding how the loss of functional variants in GIGYF1 leads to such a significant increase in the risk of developing type 2 diabetes. Their future studies will also explore other links between biomarkers of biological aging in adults and metabolic disorders.
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