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World-leading research paves the way to understanding genetic risks of CKD

17 August 2022

Researchers at Newcastle University have found that a relatively common change in a specific gene plays an important role in developing kidney failure and its presence suggests a higher risk of developing chronic kidney disease (CKD). 

Although there are many causes of CKD, changes or variations to some genes (known as mutations) are associated with an increased risk of developing CKD. One such gene is called Uromodulin (UMOD) gene, which this Kidney Research UK-funded project was investigating.  

Professor John Sayer in his lab

Let’s break it down

Think of words. Words are made up of letters. If the letters in a word change, the word also changes and probably won’t make sense. It’s the same with genes. Genes (the words) are made up of DNA (the letters). Our genes are a combination of these “letters”. Since the function of a gene is to produce proteins, if there are changes in the DNA, the gene also changes, and this can affect the protein that is produced, which can affect the way the protein works in the body. 

This is the case for the UMOD gene which is found in the kidneys and helps to produce a protein called uromodulin. Uromodulin is believed to help prevent urinary tract infections and kidney stones. It is also known to play a role in kidney injury. If changes or variations occur in the UMOD gene, the production of uromodulin protein and the way it works can be affected. Based on how the gene has changed, this effect is on a spectrum and ranges from rare to common and can have either a large or a small effect.  

Large effect changes to the UMOD gene are rare but can cause a condition known as autosomal dominant tubulointerstitial kidney disease (ADTKD) which can be inherited from one generation to the next. Smaller effect changes to the UMOD gene are more common and may be related to kidney function and the risk of developing CKD. However, researchers were yet to find if an intermediate change exists and if, similar to the large and small effect changes, would also play a role in CKD progression and risk.  

Completing the spectrum 

To complete the UMOD spectrum, researchers across the UK and EU carefully analysed large genetic data and families with inherited kidney disease and found a relatively common change in the UMOD gene which has intermediate effects. They showed that this change plays an important role in increasing the risk of developing kidney failure, although it causes less severe disease than typical ADTKD.  

This finding is important because it shows that changes to the UMOD gene can cause both rare and common forms of kidney disease at different degrees, ranging from mild to severe. It adds to what researchers know about the role of UMOD gene in kidney disease and has implications for many hundreds of patients.  

Dr Eric Olinger, first author of the paper and recipient of funding from Kidney Research UK said,

“Although we know that kidney function and the risk of CKD can be genetically determined, we do not yet completely understand the genetic landscape of kidney disease. Our findings show that intermediate effect variants, which are particularly difficult to detect and investigate in a kidney-specific gene, contributes to the genetic risk of CKD.  

“This means that a considerable number of individuals with these intermediate variants in UMOD might be at higher risk of developing CKD, although not all of them will end up with kidney failure. Further studies are needed to establish whether there are more variants that are in this ‘grey area’ of CKD risk, the lifetime risk of these people developing CKD, and whether there are other factors contributing to this genetic risk” 

Professor John Sayer, one of the senior authors of the paper added: “Importantly, our study also helps to better understand the pathophysiology of UMOD, one of the most important genes determining kidney function. This work is world leading and paves the way to understanding genetic risks of CKD” 

Kidney Research UK’s director of research, innovation and policy, Dr Aisling McMahon said: “Unfortunately, many people are at the mercy of their genetic heritage and may be unaware of their increased risk of developing kidney disease making the discovery of the UMOD gene’s impact increasingly important. The additional knowledge the research team are contributing offers hope of better treatments and earlier diagnosis to hundreds of potential patients”. 

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