Treatment of endometriosis: study on link to genome offers hope



Treatment of endometriosis: Up to 10% of women suffer from endometriosis worldwide. The disease is chronic, extremely painful, and can lead to infertility. Endometriosis occurs when tissue similar to the lining of the uterus (the endometrium) grows outside the uterus, in the abdominal cavity, and sometimes on the ovaries and fallopian tubes. These tissues respond to hormonal signals of the menstrual cycle just like the endometrium, which can cause severe pelvic or period pain.

How and why endometriosis develops is unknown â € “ and currently there is no cure. Although treatments such as pain relievers, surgery, and even hormonal contraceptives are available, they don’t always work and many women find them insufficient.

But our recent collaborative study may have brought us closer to a potential new treatment target. We have found that DNA variations in the gene that produces the neuropeptide S receptor 1 (NPSR1) protein occurs more often in women with endometriosis than in women without the condition. NPSR1 plays a role in the transmission of nerve signals and in inflammation.

Our team at the University of Oxford have been working for decades to understand which genes cause endometriosis. We first began to conduct our research after observing that the disease can run in families â € “ and that up to 50% of the risk of endometriosis in women is due to genetics. But finding the genes that cause the disease was no easy task. Endometriosis is complex and influenced by many factors â € “ including a person’s genetic makeup, environment and how these two factors interact.

To see what was different in the genetic makeup of patients with endometriosis, we analyzed the â ?? genome? the full set of genes that everyone carries â ???? women with endometriosis and a family history of the disease, and those with no known family history. We then compared their DNA to that of women without endometriosis. In total, we analyzed the genomes of 32 families with at least three women with endometriosis and 105 women without endometriosis. We also looked at another set of genetic data from over 3,000 endometriosis cases and 2,300 controls.

Familial analysis first narrowed down the cause to an area on chromosome seven, which contains around 100 genes. It was only after more extensive and detailed DNA sequencing that we discovered that it was the NPSR1 gene that carried significantly more harmful variants in women with endometriosis than other genes in the area. of chromosome seven. Women without endometriosis more often had the normal NPSR1 gene.

To further confirm these results, our collaborators at the University of Wisconsin-Madison and Baylor College of Medicine then checked for DNA variations in a colony of rhesus macaques. These monkeys have rules like humans â € “ and also get endometriosis. Indeed, we found that changes within the same region on the macaque equivalent of human chromosome seven occurred more often in monkeys with endometriosis.

After confirming this link, the next step in our research was to test whether stopping NPSR1 activity had an effect on the inflammation associated with endometriosis. To do this, we first conducted experiments using cells and then mice. Our team and collaborators at the German pharmaceutical group Bayer found that if we shut down the activity of NPSR1 in immune cells, they become less reactive and produce less of a protein that normally causes inflammation. The mice in turn showed less inflammation and suffered less than without the treatment.

However, the drug that we used in these experiments is what is called a “tool compound” ???? a???? which means it is only approved for use in cell and animal experiments, but cannot be used on humans. The next step in the research will be to find a drug that can be used in humans to similarly stop the activity of NPSR1 and see if that also reduces the symptoms of endometriosis.

Understanding NPSR1

There is still a lot we don’t know, however. For example, how exactly is NPSR1 connected to endometriosis â ???? and what is it doing (or not doing) that leads to the inflammation and pain? It will also be important to find out how DNA variants of NPSR1 affect protein function, and in which tissues.

Interestingly, NPSR1 also plays a role in the inflammation that occurs with other health issues, including asthma and inflammatory bowel disease. It is also found in certain areas of the brain, where it has effects on anxiety and behavior. This could mean that NPSR1 could play a role in the perception of pain and in the anxiety that accompanies endometriosis.

Chronic suffering and exposure to pain also changes the architecture of the brain â € “ which means that the wiring of brain cells and nerves reacts differently and changes over time. It is also possible that the link between NPSR1 and endometriosis occurs not only in inflammation and abdominal pain, but also in the brain itself. This is another aspect of NSPR1 that will need to be explored.

Regardless, our research has shown that stopping this receptor relieves pain and inflammation in mouse models of inflammation and endometriosis. This opens up the future possibility of developing drugs against NPSR1 that would relieve the symptoms of endometriosis without stopping the menstrual cycle, and potentially provide pain relief for millions of women.

Krina Zondervan, Professor of Reproductive and Genomic Epidemiology, University of Oxford and Thomas Tapmeier, Senior Women’s Health Researcher, Monash University first published this article on The Conversation.

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