Knowing that this specific gene can cause endometriosis could lead us to better treatments


A rigorous international investigation into the genetics of endometriosis has revealed a potential new therapeutic target for what remains a very common and incurable disease.

Endometriosis occurs when tissue similar to the uterus grows outside the uterus, often causing chronic pain, but not in all cases.

After decades of neglect by researchers and doctors, the reality is that we still know very little about this inflammatory disease, which primarily affects women of childbearing age.

Treatments currently include surgery to remove endometrial damage and hormones to control their growth, but both have imperfect results and come with their own risks and side effects.

Alternative treatments are desperately needed, and because endometriosis is often inherited, drug researchers are turning to genetics for clues.

The first parallel investigation of humans and rhesus macaques (Macaca mulatta) has now revealed a possible direction for future drug treatment; it is the one that is not based on hormones, which can lead to many side effects.

It started with a 2015 study at the University of Oxford on 32 families with at least three patients with endometriosis. Here, researchers discovered a genetic link between stage III / IV endometriosis and a region of the human chromosome called 7p13-15.

It was a good place to start, but this region alone contains hundreds of genes. In the end, it took several more years of research at Baylor College of Medicine in Texas to locate the specific gene the researchers were looking for.

When the researchers sequenced the DNA of 849 macaques – 135 of which had developed spontaneous endometriosis – they noticed a variation in the NPSR1 gene, which is located on chromosome 7p13-15 and appears to increase one’s risk of suffering from endometriosis. advanced stage.

Back in Oxford, the researchers sequenced the DNA of more than 11,000 women, including 3,000 women with endometriosis, to see if they could find a similar genetic variation in men. Their results finally revealed that stage III / IV endometriosis is associated with the same specific variant of the NPSR1 gene as that found in macaques.

In the past, variations in the NPSR1 gene have been linked to several other inflammatory conditions, such as asthma, allergies, inflammatory bowel disease (IBD), rheumatoid arthritis, and recurrent abdominal pain – some of which are known to coexist with endometriosis. .

But the variation, in this case, was slightly different from what has been found before with, say, IBD.

“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 complex and common metabolic diseases,” said Jeffrey Rogers of Baylor College of Medicine.

“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.”

In recent years, a growing number of researchers have come to suspect that endometriosis is not just a disease, but actually consists of several different subtypes.

There has even been preliminary evidence that the different stages of endometriosis are genetically distinct, but as of yet, there are no drugs available that target these specific variations.

The advanced stages of endometriosis are generally defined by a higher number of lesions with deeper infiltration, and yet this does not always correspond to greater pain or worsening of symptoms.

The way endometriosis presents itself can vary widely from patient to patient, and no one is quite sure why or how best to treat the various symptoms.

Even in current research, not all endometriosis patients studied at the University of Oxford had an NPSR1 variant, meaning that if a drug can be developed to target this subtype, it likely won’t work. not for everybody.

Still, that doesn’t mean it’s not worth pursuing. When the researchers inhibited the expression of the NPSR1 gene in mice, which had small pieces of uterine lining implanted in their abdomen to mimic endometriosis, the animals showed signs of reduced inflammation and abdominal pain.

“We need to do more research on the mechanism of action and the role of genetic variants in modulating the effects of the gene in specific tissues,” says genetic epidemiologist Krina T. Zondervan of the University of Oxford.

“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.”

As in any emerging field, this study has its limits. A relatively small number of patients were initially studied at the University of Oxford and the functional effects of changes in the NPSR1 gene could not be studied.

While the mice appeared to see their pain decrease somewhat when this genetic variant was turned off, Stacy McAllister, an endometriosis researcher at Emory University who was not involved in the study, said Scientific journal she would like to know if the results can be extended from the relief of acute pain to the relief of chronic pain, which is the main complaint of patients with endometriosis.

Also, because mice don’t have their period, their models of this suspected inflammatory disease can’t tell us the same. The authors of the present study admit that their results do not present the “full spectrum of disease” or “pathological nuances” that we have seen in humans.

As such, they hope to conduct further research on NPSR1 variants and their functional effects in macaques. If researchers can target the gene in monkeys the same way they do in mice, we can start testing some drug treatments, progressing to clinical trials in humans.

This reality is still a long way off, but given the debilitating toll endometriosis can have on the lives and livelihoods of women around the world, it is critical that we find a better way to treat this disease.

The study was published in Science Translational Medicine.

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