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Genetic link to common cause of kidney disease in children identified

16 November 2022

Babies born with posterior urethral valves (PUV) have a thin piece of membrane blocking the exit of their bladder. This barrier prevents urine from leaving the body and can lead to kidney damage. PUV is found in 1 in 4,000 male babies; it is the most frequent cause of end-stage kidney disease in children. Exciting research from Dr Melanie Chan and her team at University College London has provided new insights into the causes of PUV, and demonstrated a new approach to genetic analysis, which is more inclusive of people from different backgrounds. 

PUV in children: an unmet need

PUV cases are often identified during routine pregnancy scans, when healthcare professionals check the developing kidneys and bladder of an unborn baby. However, even with early detection and corrective surgery, more than a third of patients with PUV will need a kidney transplant or dialysis before the age of 30. 

Our understanding of what causes PUV is currently limited, and there is an unmet need to improve outcomes in these patients. Inspired by her work as a doctor treating patients with kidney disease, and family experience of inherited kidney disorders, Dr Chan and her team, supported by a research grant from Kidney Research UK, investigated whether specific changes in DNA might be linked to PUV. 

Dr Melanie Chan
Dr Melanie Chan

Dr Chan said "Although PUV is not a common disorder, many of the boys who are born with this condition develop kidney failure and long-term bladder problems. We thought that there may be a complicated genetic link, and technology now allows us to look carefully at DNA for changes that might be linked to rare diseases such as PUV."

A new approach to learning from DNA

Dr Chan analysed genetic material (DNA) from 132 people with PUV recruited to the 100,000 Genomes Project (a UK-based initiative to help find DNA links to rare diseases) and 23,727 individuals without PUV (controls). She used a technique called GWAS and the results were confirmed in patients with PUV from other European countries.

Dr Chan discovered two new genes linked to PUV: TBX5 and PTK7. TBX5 is a transcription factor which acts like a switch to turn other genes on and off and PTK7 helps cells to line up correctly during development. Importantly, this study showed that both of these proteins are seen in the developing  urinary tract, providing a target for future investigations. 

What is GWAS?

A GWAS is a genome-wide association study which compares the genetic material of people with and without a particular disease to see if there are any differences. In this study, a new version of this technique, seqGWAS, was used to allow identification of rarer, and harder to detect, genetic changes. 

Implications beyond kidney disease

This research is important not only for improving our understanding of PUV, but also for other researchers looking at genetic links to diseases. Most genetic studies only look at European populations but in this study individuals with different genetic ancestries, including people of South Asian, African, and European descent were included, showing that using diverse genetic samples can allow researchers to find out new information about rare diseases. 

Senior author Professor Daniel Gale commented that "Most previous genetic studies of this nature have used individuals with a single genetic ancestry (usually Europeans) but this can miss effects that are important in other populations. By using whole genome sequencing data, we were able to include people from many different ancestral backgrounds which is not only more inclusive but also increased our power to detect the key genes in PUV. Inclusivity is important because it helps more people benefit from treatment advances driven by genetic discoveries, so we hope this study will encourage researchers to use more diverse populations in future genetic studies."

Professor Daniel Gale
Professor Daniel Gale

Dr Aisling McMahon, Executive director of research and policy at Kidney Research UK said:We were delighted to support Dr Chan and her team in their work, not only into the genetic causes of PUV, but also in their efforts to demonstrate how research can be more inclusive. At Kidney Research UK we are committed to ensuring that our scientific studies are as relevant as possible to all members of the kidney community, and this work represents an important step forward for trials looking at genetic causes of diseases. 

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