Current Research on Endometriosis: An Interview with Grant Montgomery
Charlotte Weber: Could you please introduce yourself briefly?
Prof. Grant Montgomery: My name is Grant Montgomery. I am a research fellow at the Institute for Molecular Bioscience at the University of Queensland in Brisbane, Australia. I started working in the endometriosis field when I moved to Australia over 20 years ago and joined a group that had recently started a program on the genetics of endometriosis. Currently, I am the Director of the Center for Population and Disease Genomics at the IMB and my laboratory continues research on endometriosis. Our program started out working on the genetics of endometriosis but has now expanded into several other projects.
Charlotte Weber: What fascinates you most about the topic? What’s your main motivation?
Prof. Grant Montgomery: I have a background in reproductive biology and genetics. When I joined the Queensland Institute of Medical Research, twin studies by Susan Treloar comparing identical and non-identical twins had shown there was a strong genetic contribution to risk for endometriosis and also uterine fibroids. They chose to follow up these studies and started a major program on the genetics of endometriosis. With my background in molecular genetics, led molecular studies for the program and later took over the leadership.
I’ve been working on the program now for over 20 years. The disease is a real burden for many women who suffer from endometriosis and I continued to work on that project after I moved to the University of Queensland.
Charlotte Weber: Could you summarize your work for our readers?
Prof. Grant Montgomery: The twin studies showed about half the risk for endometriosis is the result of genetic factors and the other half from environmental factors. The aim of our program is understand the genetic risk factors to help us understand the causes of the disease. It’s taken us much longer than we would have hoped to do that. We started by recruiting women with endometriosis including sisters who both had a confirmed surgical diagnosis of endometriosis and we still include results from that group of patients in our studies today. We’ve conducted a number of genetic studies, but success in discovering genetic risk factors linked to endometriosis came with the ability to genotype lots of markers across the genome as genotyping chips became available and cheap enough to do quite large studies. Together with the International Endometriosis Genetics Consortium we’ve completed a series of increasingly large studies to map the genetic risk factors.
The latest International Endometriosis Genetics Consortium paper came out a couple of months ago and that’s a study of over 60,000 women with endometriosis compared to a very large control group of about 700,000 individuals. In that study, we identified 42 genomic regions that contribute to the risk of endometriosis and 31 of those were novel. They hadn’t been seen in the earlier studies. We now have a good handle on what regions of the genome contribute to risk. We continue to do genetic studies but we are now trying to understand how those genetic risk factors change the programs of cellular biology and gene expression. This has proved to be much more difficult than we’d hoped not just for endometriosis but for most complex diseases because most of those genetic risk factors are not within the coding parts of genes.
They are located in other parts of the genome, within the introns, and also in the regions between the genes. We think that many causal variants will be found in the regulatory regions of the genome, which control how genes are regulated in individual cells. We really didn’t have a good map for that. That’s one of the reasons why it’s proved more difficult than we would have hoped. I think another reason is that that program is a bit different for different cell types. What cell type contributes to the cells that start the lesions in endometriosis and which cells are important? We need to be able to look at the individual cell types and have not had good methods to do that until quite recently. Advances in cell biology and advances in genomics are coming together to try to make this possible.
Charlotte Weber: What are your research goals for the future or what are the other projects you will be working on?
Prof. Grant Montgomery: We continue the genetics projects. We are trying to understand how those genetic variants influence the programming of cells and the gene expression in the individual cells. What we think is that in many cases the cells that initiate the lesions come from the endometrium through retrograde menstruation. We’re still working on understanding the regulation of the expression in the endometrium. We’re also now looking at the lesions themselves and have quite a big program on cell biology in the lab. We work with clincians at the Royal Brisbane and Women’s Hospital in Brisbane to recruit patients for the studies. We grow the different sorts of cells in the lab and are able to culture the different cells together to try to understand how that all works.
We also have quite a big program with Professor Gita Mishra, who is the University of Queensland lead for a big study called the Australian Longitudinal Study on Women’s Health. They have about 60,000 women in their study. We’re looking at the incidence of endometriosis in the Australian population and the consequences for patients in terms of their health services use, pharmaceutical use, and effects on their life course? The other program of work that’s in the lab is trying to understand the comorbidity between endometriosis and related diseases. We work with public databases and our own studies to try to understand the relationship between endometriosis and other diseases like uterine fibroids, ovarian cancer, and gastrointestinal disorders identifying shared genetic risk factors and implications for clinical management.
Also, we are trying to think about whether we can improve early diagnosis by looking at patient-reported symptoms and clinical data that we can put together to develop an improved diagnostic questionnaire. The other big thing that motivates the lab now is to try to understand whether there are subtypes of the disease. This is because endometriosis is so variable between patients. The lesions are found in different locations. There’s not a good correlation between the presence of lesions and symptoms. Is it just an extremely variable disease or are there really subtypes of endometriosis, as we’ve seen for some of the cancers? I think that is one of the critical questions that we really need to address because clearly in terms of personalized treatments, understanding the subtypes of cancer has had a big impact.
We’re doing quite a lot of work both ourselves, our colleagues and with the International Endometriosis Genetics Consortium to try to address this. If we can discover markers for distinct subtypes it would will flow into ways of providing more personalized treatments downstream. We need to do the work first before we can predict what they’ll be.
In summary, the big questions we are trying to address at the moment is whether there are distinct subtypes of endometriosis that would explain the variation in disease presentation and how can we use the current information to help with earlier diagnosis.
Charlotte Weber: Okay, that’s two parts that your work contributes to the diagnosis and to the therapy.
Prof. Grant Montgomery: All of the things that I’ve been talking about feed into that. The genetic studies that we’ve done try to understand how the genetic risk factors change the biology and therefore contribute to disease. We recruit participants for large studies where we’ve got good clinical data on the clinical presentation and collaborate with other colleagues notionally and internationaly to have sufficient power for meaningful answers. Our epidemiology studies with the Australian Longitudinal Study on Women’s Health cell biology and genomics studies all contibute to help us think about earlier diagnosis and better ways for more personalized treatments.
One approach being taken by Dr Sally Mortlock, one of the scientists who works in my group, is to look at the genetic correlations that exist between endometriosis and other traits and diseases. One of the advantages of all the genetic data that are now available is the expanding datasets available on genetic risk factors for traits and diseases from many independent studies. We can use that information to look at the overlap in related conditions in more depth looking at genetic correlations and causes and consequences of this overlap. Sally and her colleagues and students have demonstrated genetic overlap between endometriosis and a number of traits and diseases, including various pain conditions, other reproductive traits, ovarian cancer, and gastro-intestinal disorders. For example, recent results show endometriosis was genetically correlated with common gastrointestinal disorders including irritable bowel syndrome (IBS) and gastro-oesophageal reflux disease (GORD) with evidence for genetic risk factors for IBS and GORD affecting endometriosis risk. These results explain why symptoms for endometriosis and gastro-intestinal disorders may overlap and sometimes lead to misdiagnosis and delay in treatment for endometriosis.
Charlotte Weber: I think it’s easy to understand that what you’re doing is you’re working on different parts of the disease like we said on the diagnostic part and the therapy part of understanding other diseases that are related to endometriosis. That is a lot of work you’re doing and I think that we really got that message.
Prof. Grant Montgomery: One reason to be optimistic is despite slow progress to date because endometriosis is quite a difficult disease to work on because of the variation in presentation, the genomics and cell biology methods available and the degree of resolution of the genome methods has really changed in the last five years. I think that if we can put all these methods together and use the information and new methods intelligently, we can expect to see a lot of progress in understanding the disease over the next five to 10 years. If we can combine this new data with detailed patient and clinical information, we really hope to be able to make a lot of progress in understanding the disease in ways that we haven’t been able to do before.
It’s not that we can solve the problems tomorrow, but I think there’ll be a lot more progress in the next 20 years than I’ve seen in the last 20, let’s put it that way. Some of that will really impact patients.
Charlotte Weber: I think all of it will impact patients, maybe not in ways that they realize but it definitely will in many aspects. Okay. Thank you very much for talking to me today and taking the time.