Identifying the Endometriosis Gene 

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Mark Perloe, MD: “I’m Mark Perloe. I’m here at the American Society of Reproductive Medicine meeting in Seattle, and just heard a wonderful round table luncheon discussion by Dr. Stephen Kennedy from the University of Oxford, department of OBGYN, and I guess I want to start off to ask you to let our listeners know, our viewers know, whether we’re on the verge of finding an endometriosis gene?”

Stephen Kennedy, MD: “Mark, I think that within about five years we will have identified at least one gene that makes it more likely that women develop endometriosis and that will have profound implications for the way in which the disease is managed.”

Mark Perloe, MD: “We’ve been taught in medical school, that Sampson’s Theory, that there is too much endometrium coming back into the peritoneal cavity or that the tissue is stickier or it’s more likely to invade or there are disorders in the immune system that lead to this condition. Might not there be variability in the genes that affect each of the steps between menstruation and the development of clinical symptoms?”

Stephen Kennedy, MD: “I think that’s quite likely, I agree with you, but what I also think is likely to emerge from the sort of research that is going on is that we’ll be able to divide endometriosis up, into separate conditions. In other words, the traditional teaching that endometriosis is a single disease spectrum represented from mild to severe and a condition that progresses in some women, I think will prove not to be the case. I think what’s much more likely to emerge from the genetic dissection of this disease is that we’ll come to understand that there are a number of different conditions, with different etiologies and different manifestations that can co-exist in some women. In other words peritoneal endometriosis may arise as a consequence of retrograde menstruation but ovarian disease I’m sure arises much more likely because of some metaplasia process within the ovary and then on top of that there are some women that also develop adhesions irrespective of how much disease they have in the pelvis.”

Mark Perloe, MD: “One of the things as a clinician that frequently happens is that the patient may come in for pain or may come in for endometriosis and fertility evaluation and suspects that she is dealing with endometriosis, and laparoscopy may be part of the evaluation to confirm the diagnosis. The next step is obviously surgical treatment. They are wanting to know, so what does this mean for me what are the implications down the line? In the past, physicians have told patients to go home and get pregnant if they make a diagnosis of endometriosis. Do you believe that the genetic information and the dissection of this condition into different entities will allow us to better advise women on what the outcome or progression of the disease may be?”

Stephen Kennedy, MD: “I think that is likely, remember this is all speculation because we are just at the beginning of our understanding of the extent to which genes contribute to this disease. But I think it’s likely that we’ll be able to say to some women it’s more probable than not that you will develop severe disease over time and it’s more probable than not that that will cause infertility. And I think being able to predict which women are likely to develop the worst manifestations of the condition will have a profound effect on women in general. For example, some women, and again this is all speculation at present, but some women who are found to have a susceptibility and predisposing them to the development of severe endometriosis causing infertility may decide that actually they are going to have children earlier in their life and not delay childbearing for professional reasons. I think that will be a major contribution to women in general.”

Mark Perloe, MD: “In the genetic course earlier this weekend we were told that in about five years we will all be given a credit card copy of our DNA code. Do you expect that these women who are at risk may be identified before they become symptomatic?” 

Stephen Kennedy, MD: “That’s a possibility. I read it in a newspaper just this week that there is an American company that can now perform a genome wide SNP analysis for individuals at the cost of, I think about, $20,000 – $30,000. That will become a reality over time. And yes, it may be possible to have in the office, I’ve no idea how long, a chip that you just drop a little bit of blood on and it tells you what your susceptibility is for a whole variety of conditions, not just endometriosis.” 

Mark Perloe, MD: “We also heard about targeting drug therapies so that we can determine which drug might work best. Do you see this research opening up new fields of pharmacological manipulation of woman with endometriosis?”

Stephen Kennedy, MD: “Oh, very much more so. I take a very cynical view of the role of medical therapy at present. It’s a blunderbuss approach, switching off ovarian function in the hope that it will relieve symptoms. The fact is, that for many women it’s very effective but only whilst the woman remains on the drug. But we don’t understand which mechanisms are malfunctioning to cause the disease itself or to cause the symptoms associated with the disease. Understanding the genetic basis of endometriosis should in theory lead to targeted therapy, hitting those particular pathways which are aberrant in some women with the disease but not others.”

Mark Perloe, MD: “How do you identify candidate genes? I know that your research is in this area. There are a lot of genes that we have to look at and how have you targeted your focus in the area of endometriosis?”

Stephen Kennedy, MD: “There are two different approaches to the identification of candidate genes. One is the functional approach and the other is a positional cloning approach. The functional approach is very simple. What is says is you choose candidate genes on the basis of what is known presently about the disease, so what is biologically plausible? For example, oestrogen receptive polymorphisms, one can speculate, should somehow be involved in disease aetiology if not progression, because endometriosis is an oestrogen receptive condition. So that’s how functional candidate genes are chosen and usually what one does is look to see whether the frequency of a particular polymorphism in one of these candidate genes occurs more commonly in the affected population than in the controls. Although we have done some studies on functional candidate genes our principal approach has been positional cloning. And that approach it’s not hypothesis driven. What one’s saying is, ‘I don’t know which biochemical mechanisms are malfunctioning in endometriosis. I don’t know which genes are involved.’ What one does is search through the entire genome looking for chromosomal regions that are inherited within families more commonly than would be expected by chance alone. Having identified those chromosomal regions one then hones down even further to look for genes within those regions that have biological plausibility. And so at that point, you look for polymorphisms in these positional candidates in affected cases and controls. So they are two entirely different approaches and it’s the positional cloning approach that we, in collaboration with Nick Martin’s Group in Australia have adopted for the search for endometriosis genes.”

Mark Perloe, MD: “Have you any suspects to share with us today?”

Stephen Kennedy, MD: “The commercial sensitivity of the data inevitably means that I can’t do that.”

Mark Perloe, MD: “It’s just like watching CNN and the sniper investigation that’s going on now. I guess we’ll have to just stand by and watch.”

Stephen Kennedy, MD: “Well, my wife is very worried about me flying to Washington this evening. I’ll stay in my hotel room.”

Mark Perloe, MD: “I think that’s great. Well, we’ll look for more results and follow your research. Thank you so much for joining us.”

Stephen Kennedy, MD: “Thank you very much Mark.”

See also Genetic Epidemiology of Endometriosis