By Stephen Kennedy
Senior Fellow in Reproductive
Medicine, University of Oxford

Despite extensive research over the last 20 years, we still do not understand why endometriosis occurs or why it causes pain and infertility. It is, therefore, a very difficult condition to treat.

There is now evidence that genetic susceptibility may be important, e.g., some women are born with genes that make it more likely that they will develop the disease. This raises the possibility that the genes can be identified, using new molecular biology techniques, which should lead to a better understanding of what causes endometriosis and its awful effects on women. The type of research is called "linkage analysis" or "reverse genetics." Similar research in other common conditions such as asthma, hypertension and diabetes is being done and may, in time, lead to more effective treatment.

Genetic susceptibility is likely because: a) endometriosis tends to run in families; b) there are reports of endometriosis in identical twins; c) the disease is 6-9 times more common in the sisters of affected women than amongst women in the general population; and d) sisters tend to develop pain symptoms at the same age. These are all features that one would expect if endometriosis had a genetic basis.

It is unlikely, however, that it is inherited in a simple "Mendelian" fashion (like cystic fibrosis, for example, which is autosomal recessive). It is more likely that endometriosis is a "multifactorial" condition, i.e., a number of genes interact with each other and environmental factors (possibly dioxins or irradiation) to increase the chances of a woman developing endometriosis. This means it is not inevitable that a woman will develop endometriosis if she inherits the genes; she is simply more likely to do so than a woman without the genes.

It is the aim of the Oxford Endometriosis Gene (OXEGENE) Study, a collaborative project between the University of Oxford and leading researchers around the world, such as David Redwine, MD, to identify susceptibility genes for endometriosis using this technology. The study involves collecting blood from sisters with surgically confirmed AFS moderate-severe (III-IV) disease and their parents for DNA analysis in our laboratories. The type of analysis is called the "affected sib-pair" method. The first step involves finding tiny portions of chromosomes that are inherited from the parents of the affected sisters more commonly than one would expect by chance alone. One then tries to isolate individual genes in the tiny portions of chromosomes. Once the genes have been isolated, one can study their function and thereby understand better why it is that endometriosis grows in the way that it does. We have deliberately chosen to investigate women with moderate-severe disease in the first instance because if there is a genetic effect, we are more likely to find it by studying women with the more severe forms of the disease.

In time, however, we hope to ask sisters with minimal-mild endometriosis to participate as well. Affected families are being recruited in four ways:

• Through advertisements placed in the newsletters of national endometriosis self-help groups, e.g., the National Endometriosis Association in the USA;
• With the collaboration of leading research centers throughout the world via the OXEGENE web site http://www.medicine.ox.ac.uk/ndog/
• In Oxford alone, by screening the sisters of women with moderate-severe disease using magnetic resonance imaging.

Through the endometriosis self-help groups and the web site, the Oxford Group has contacted 435 families containing 703 affected women from the UK (342), USA (285), Australia (23), Canada (17), New Zealand (15), Ireland (10), Italy (3), Germany (2), Holland (1), Israel (1), Philippines (1), Mexico (1), Sweden (1), and Slovenia (1). These families contain 56 sister-pairs with stage III-IV disease. The collaborators have so far identified a further 167 sister-pairs with stage III-IV disease. Additional collaborators are joining the OXEGENE Study all the time as we continue to collect as many sister-pairs as possible.

In the long-term, this research may lead to a better understanding of the disease, new treatment methods and possibly even a blood test to give women an estimate of their risk of developing endometriosis.

Stephen Kennedy
Senior Fellow in Reproductive Medicine/Honorary Consultant, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital
Oxford UK 0X3 9DU