Researchers identify genetic cause of endometriosis, reveal potential drug target

Endometriosis is a painful, chronic disease in which tissue in the uterus inappropriately grows outside the uterus. Current treatments are limited and include surgery and hormone therapy, which can cause unwanted side effects. New research from Baylor College of Medicine, University of Oxford, University of Wisconsin-Madison and Bayer AG, offers new insights into how to treat this debilitating disease.

The researchers performed genetic analyzes of humans and rhesus macaques to identify a specific gene, NPSR1, which increases the risk of suffering from endometriosis. The results reveal a potential new non-hormonal drug target that could lead to improved treatment. Their results are published in Science Translational Medicine.

The Oxford team, led by corresponding author Dr Krina T. Zondervan, had previously found a genetic link to endometriosis on chromosome 7p13-15 by analyzing DNA from families containing at least three diagnosed women. with endometriosis. The Baylor team, led by lead author Dr. Jeffrey Rogers, verified this genetic link in the DNA of rhesus monkeys with spontaneous endometriosis at the Wisconsin National Primate Research Center at the University of Wisconsin-Madison. This validation warranted further research through an extensive sequencing analysis of endometriosis families at Oxford, which reduced the genetic cause to rare variants of the NPSR1 gene. Most women with these rare variants had stage III / IV disease. Baylor researchers similarly sequenced rhesus monkeys and again showed suggestive evidence in this species as well. Finally, an Oxford study of over 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant of the NPSR1 gene also associated with stage III / IV endometriosis. .

“It is one of the first examples of DNA sequencing in non-human primates to validate the results of human studies and the first to have a significant impact on understanding the genetics of common and complex metabolic diseases,” said Rogers, associate professor at Human Genome Sequencing. Center in Baylor. “The primate research has really helped build confidence in every step of genetic analysis in humans and has motivated us to keep chasing these particular genes.”

The information revealed in this genetic analysis points to a potential new drug target. As part of this collaboration, researchers at Bayer, in scientific partnership with the University of Oxford, used an NPSR1 inhibitor to block protein signaling of this gene in cellular tests and then in mouse models of endometriosis. They found that this treatment reduced inflammation and abdominal pain, thus identifying a target for future research in the treatment of endometriosis.

“This is an exciting new development in our quest for new treatments for endometriosis, a debilitating and underestimated disease affecting 190 million women worldwide. We must continue to research the mechanism of action and the role of genetic variants in modulating gene effects in specific tissues. However, we have a promising new non-hormonal target for further research and development that appears to directly address the inflammatory and painful components of the disease ”, said Zondervan, head of the women’s and reproductive health department, professor of reproduction and genomic epidemiology and co-director of the Endometriosis CaRe Center in Oxford.