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New research identifies genomic mutations linking liver disease, diabetes, and obesity

Published today in Nature (13th October), Convergent somatic mutations in metabolism genes in chronic liver disease details research leading to new understanding about how systemic diseases interact

Dr Stanley Ng, first author, Hughes Hall Research Associate and Postdoctoral Fellow at the Wellcome Sanger Institute, said: “Liver disease is a complex disease that often sits at the centre of other issues and conditions such as obesity and type 2 diabetes. However, the relationship between these diseases is poorly understood. This research leads to fascinating new understanding of systemic diseases and how to diagnose, manage and treat them.”

Patients with liver disease associated with obesity, type 2 diabetes and chronic alcohol consumption have been found to have acquired specific DNA mutations in their liver cells that disrupt fat metabolism and insulin sensitivity.

The collaboration between the Wellcome Sanger Institute, the Cancer Research UK Cambridge Institute and others, identified five genes that are mutated in individuals with liver disease – the third leading cause of premature death in the UK. Its most common causes include chronic alcohol consumption and non-alcoholic fatty liver disease (NAFLD), which are linked to obesity and type 2 diabetes. When there is high consumption of alcohol or calories, insulin signals to the liver cells to take up, process and store a large amount of fat. If this is sustained for long periods of time, the burden of storing this excess fat damages the cells, leading to inflammation, chronic liver disease and ultimately cirrhosis of the liver.

Whilst these processes are occurring, however, liver cells can acquire mutations that change the way they react to insulin signalling. Upon acquiring some of the mutations identified in this study, these cells no longer take up excess fats, which enables them to escape the associated toxicities. This provides them with a survival and growth advantage over other liver cells without these mutations. However, although these mutations provide a selfish benefit to the individual liver cell, they may impair that cell’s ability to contribute to the function of the liver as a whole.

Dr Peter Campbell, senior author and Head of Cancer, Ageing and Somatic Mutation, and Senior Group Leader at the Wellcome Sanger Institute, said: “This is the joy of science – we started this study hoping to understand how liver cancer emerges from chronic liver disease, but instead wind up proposing an exciting new model in which the same genetic event is acquired many times independently within the liver, collectively accounting for a considerable fraction of liver cells. The mutations might protect the liver cells from toxicity, but only by enabling those cells to shirk their metabolic duties.”

Remarkably, many of the patients studied had multiple independent occurrences of mutations in metabolism genes. In some cases, it is estimated that these mutations cumulatively affected up to 15-25 per cent of the entire liver. Such a high burden of liver cells carrying mutations that impair their handling of dietary nutrients could lead to organ-wide changes in liver function. Within a given patient’s liver, the same metabolism gene was often recurrently mutated. However, between different patients, the specific mutations observed frequently diverged, suggesting that it might be possible to stratify liver diseases into refined subgroups according to their patterns of mutations.

The research could lead to a potential new model for understanding how mutations in specific cell types can contribute to diseases such as diabetes. With further investigation, it may be possible to develop and match novel treatments to mutation-based subgroups.

Stanley Ng completed his PhD at the University of Toronto, Canada, and has been a member of Hughes Hall’s Fellowship since 2019: “Hughes’s commitment to translating new findings into improved clinical practice, has always enthused me. It is a rewarding and diverse community to be part of and one I hope to play an increasing role in, alongside my research at the Wellcome Sanger Institute.”

The paper is available on nature.com: https://www.nature.com/articles/s41586-021-03974-6.

Further information

Publication: Stanley W. K. Ng, Foad J. Rouhani, Simon F. Brunner, Natalia Brzozowska, et al. (2021) Convergent somatic mutations in metabolism genes in chronic liver disease. Nature. DOI: 10.1038/s41586-021-03974-6.

Funding: This research was funded by Wellcome, Cancer Research UK (CRUK), including a CRUK Grand Challenge Award, the European Molecular Biology Organization (EMBO), and the Swiss National Science Foundation.

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