The discovery could help scientists better understand what causes a rare condition called posterior urethral valves (PUV), which affects 1 in 4,000 men and leads to blockages in the urethra and pooling of urine in the bladder, which can then damage the kidneys . About a third of people with this condition develop kidney failure before the age of 30. Affected people often have surgery to remove the blockages, but most continue to have urinary tract problems after surgery. Therefore, new insights into the cause of the condition are needed to better understand how the urinary tract evolves in health and disease, and potentially inform new treatment approaches in the future.
“PUV does not follow a Mendelian inheritance pattern, with each parent contributing one of two possible alleles for a trait, and scientists have not identified a single genetic cause,” explains lead author Dr. Melanie Chan, who conducted the study as a Clinical Research Fellow at the UCL Department of Renal Medicine, London, UK. “This suggests that the genetic basis of this condition is more complex.”
To identify the genetic causes, Chan and colleagues analyzed the genomes of 132 unrelated men with PUV and 23,727 people without the condition recruited for the UK’s 100,000 Genomes Project. They included people of diverse genetic ancestry, including people of South Asian, African, and European descent. They found two genetic variants associated with PUV risk. One was a common genetic variant on chromosome 12q24.21 and the other was a rare genetic variant on chromosome 6p21.1. They confirmed the link between these two genetic differences and the disease in a separate group of people of European descent, which included 395 men with PUV and 4,152 people without the condition.
The team then mapped the variation to a gene called 12q24.21 TBX5, which helps turn other genes on or off. They also mapped the 6p21.1 variant of a gene called PTK7, which plays an essential role in cell development. When they looked at cells from developing human embryos, they found that the proteins encoded by the genes are active in the developing urinary tract. This discovery suggests that changes in these proteins may interfere with normal urethral development.
Finally, they showed that structural changes in chromosomes, including flipped stretches of DNA or other changes that alter the regulation of gene expression, are also associated with PUV.
“Our study is the first to identify rare and common genetic variations that are strongly associated with PUV, as well as structural variations in chromosomes that may contribute to the disease,” says Dr. Chan. “It provides new insights into what causes this poorly understood disorder.”
The authors add that the small number of people included in this genetic analysis reduces its statistical power to detect very rare genetic variations associated with PUV. Additionally, they say more studies are needed to verify exactly how these genetic changes cause PUV.
However, lead author Professor Daniel Gale, from St Peter’s Chair of Nephrology at UCL’s Department of Kidney Medicine, says the study demonstrates the importance of including people from diverse genetic backgrounds in genome-wide studies of rare diseases. He noted that genetic studies too often only include European populations, making them less likely to identify genetic variants that might be important to other groups.
‘The increasing variety of genetic studies is both scientifically and ethically beneficial,’ says Professor Gale. “It increases the power of studies to find and verify rare genetic variants and enables the detection of genetic variants that disproportionately affect people of Asian, African or other non-European ancestry.” It also helps ensure that people around the world benefit equally from treatment advances driven by genetic discoveries.”
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