Researchers identify genetic cause of endometriosis and reveal potential
drug target

Date:
August 25, 2021
Source:
Baylor College of Medicine
Summary:
New research offers insight into how to treat endometriosis. The
researchers performed genetic analyses of humans and rhesus macaques
to identify a specific gene, NPSR1, that increases risk of suffering
from endometriosis. The results reveal a potential new nonhormonal
drug target that may lead to improved therapy.



FULL STORY ========================================================================== Endometriosis is a painful, chronic condition in which tissue from the
uterus inappropriately grows outside the uterus. Current treatments
are limited and include surgery and hormone therapy, which can involve
unwanted side effects.

New research conducted by Baylor College of Medicine, the University
of Oxford, the University of Wisconsin-Madison and Bayer AG, offers new
insight into how to treat this debilitating disease.


==========================================================================
The researchers performed genetic analyses of humans and rhesus macaques
to identify a specific gene, NPSR1, that increases risk of suffering
from endometriosis. The results reveal a potential new nonhormonal drug
target that may lead to improved therapy. Their results are published
in Science Translational Medicine.

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

"This is one of the first examples of DNA sequencing in nonhuman
primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex
metabolic diseases," said Rogers, associate professor at the Human
Genome Sequencing Center at Baylor. "The primate research really helped
to provide confidence at each step of the genetic analysis in humans
and gave us motivation to carry on chasing these particular genes."
The insights revealed in this genetic analysis point to a potential new
drug target. As part of this collaboration, researchers at Bayer, in
scientific partnership with Oxford University, used an NPSR1 inhibitor
to block protein signaling of that gene in cellular assays and then in
mouse models of endometriosis. They found this treatment led to reduced inflammation and abdominal pain, thus identifying a target for future
research in treating endometriosis.

"This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognized disease affecting 190
million women worldwide. We need to do further research on the mechanism
of action and the role of the genetic variants in modulation of the gene's effects in specific tissues. However, we have a promising new nonhormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease," said
Zondervan, head of the department of women's and reproductive health,
professor of reproductive and genomic epidemiology and co-director of
the Endometriosis CaRe Centre at Oxford.

Dr. Thomas Tapmeier, now at Monash University, is co-corresponding author
of the study.

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Thomas T. Tapmeier, Nilufer Rahmioglu, Jianghai Lin, Bianca De
Leo, Maik
Obendorf, Muthuswamy Raveendran, Oliver M. Fischer, Cemsel Bafligil,
Manman Guo, Ronald Alan Harris, Holger Hess-Stumpp, Alexis Laux-
Biehlmann, Ernesto Lowy, Gerton Lunter, Jessica Malzahn, Nicholas G.

Martin, Fernando O. Martinez, Sanjiv Manek, Stefanie Mesch, Grant W.

Montgomery, Andrew P. Morris, Jens Nagel, Heather A. Simmons,
Denise Brocklebank, Catherine Shang, Susan Treloar, Graham Wells,
Christian M.

Becker, Udo Oppermann, Thomas M. Zollner, Stephen H. Kennedy,
Joseph W.

Kemnitz, Jeffrey Rogers, Krina T. Zondervan. Neuropeptide S receptor
1 is a nonhormonal treatment target in endometriosis. Science
Translational Medicine, 2021; 13 (608): eabd6469 DOI:
10.1126/scitranslmed.abd6469 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210825143114.htm

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