Decades of research has culminated in a landmark study identifying a novel genetic variant that is associated with severe cases of endometriosis. The gene is known to play a role in several inflammatory diseases and the findings direct researchers toward new non-hormonal drug treatments for the painful condition.
Affecting around one in 10 women, endometriosis is a painful condition that can lead to infertility. It is unknown what causes the endometriosis but researchers do know the condition is heritable, suggesting genetics play a notable role.
The new study, published in the journal Science Translational Medicine, builds on prior work tracking several families with high rates of heritable endometriosis. The researchers first homed in on a particular region of a specific chromosome, and then several more years of work pointed to rare variants in a gene known as NPSR1 as the common thread in many severe cases of endometriosis.
Subsequent investigations in rhesus macaques, an animal known to develop endometriosis, confirmed this particular genetic link. And finally, a large genomic survey of over 3,000 women with endometriosis confirmed the specific genetic association in a big human cohort.
"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," explains Jeffrey Rogers, senior author on the new study. "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."
NPSR1 mutations have never before been linked with endometriosis. They have, however, been associated with inflammatory diseases including arthritis, inflammatory bowel disease and asthma.
So what happens with endometriosis if expression of NPSR1 is inhibited? To investigate this question the researchers turned to a mouse model of endometriosis. When a drug was used to block NPSR1 receptors the animals showed reductions in abdominal pain and inflammation.
The researchers note the experimental NPSR1 inhibitor used in the study is not something that can be translated to humans. Instead, the experiment validated this gene’s potential role in endometriosis, and points to the development of anti-inflammatory therapeutics targeting this mechanism.
It is still early days for the research, and much more validation is needed in primate models and humans. Also, not every woman with endometriosis was found to have this particular NPSR1 variant, affirming the heterogenous nature of the condition. But the discovery raises hopes the first non-hormonal therapy for endometriosis may be on the horizon.
"This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognized disease affecting 190 million women worldwide,” says corresponding author Krina Zondervan, from the University of Oxford. “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.”
The new study was published in the journal Science Translational Medicine.
Source: Baylor College of Medicine