19th February, 2009
Epidemiology Research Platform via Ausimmune
Interview with Prof Anne-Louise Ponsonby, Head – Environmental and Genetic Epidemiology Research Group, Murdoch Childrens Research Institute
Transcript of interview
Epidemiology Research Platform via Ausimmune
Interview with Professor Anne-Louise Ponsonby, Head – Environmental and Genetic Epidemiology Research Group, Murdoch Childrens Research Institute
Ausimmune - An Introduction
The Ausimmune study was established in 2002 to investigate why there appears to be a 6-fold difference in MS prevalence rates across Australia, with increases as one moves southwards. The study is a multi-centre case control study, with 5 study sites (Brisbane, Newcastle, ACT, Geelong, Hobart) going down the Eastern seaboard of Australia.
In each of those regions, all people who develop a first de-myelinating event and present to a neurologist, or to a radiology practice for an MRI to ascertain their problem are invited to participate in the Ausimmune study for 3 years following 2002. We have had a 90% response rate, and 305 people with de-myelinating events have participated, of whom 283 have not had a previous history suggested of MS.
At the same time, we have recorded very detailed information on these people’s lifestyle, environment, and asked them to provide a blood test to look at genetic, infection and other factors. We have then gone to the community through the electoral roles and invited 1-2 controls who are age and sex matched to the case. If the case is a female presenting at age 22, then we have asked two 22 year old females in the same region to also participate in the study, and to go through a similarly lengthy interview process and to provide a blood test as comparison data.
Our hypothesis that we wish to test is that people who have their first de-myelinating have a different level of vitamin D at the time of presentation than health controls in the same area. We are also very interested in whether people who present with a first de-myelinating event have either a different pattern of infection at the time of presentation or a different pattern of host response to past infection. We can do blood tests to look at how people have responded to viruses and so on in the past. Because we want this study to be comprehensive, we have looked at a range of factors including diet, physical activity, exposure to chemical solvents, other occupational exposures and so on.
We are now at the analysis phase, and we want to only present our results when they are multi-factorial; that is, we want to present, say, the result of vitamin D and first de-myelinating event; but we need to understand how much of that vitamin D came from sun versus dietary vitamin D; do the people who have high vitamin D only have it because they are more physically active and it’s actually the fact that they’re outside and running that is the benefit rather than the vitamin D; or is it the people who have the vitamin D who have health lifestyles and they don’t smoke as much. We are trying to unravel all those related factors, which is a process we have gone through in our previous work on MS, but it is just so much more extensive this time because we have been so much more ambitious in what we’ve tried to collect at the same time.
Although we don’t understand the causes of MS, we do have some components of the jigsaw puzzle. One of them relates to the genetic profile of a person with regards to human leukocyte antigen, which is a way that people respond to infection. People with MS tend to have a different profile for that gene than other people, and that is an indication to us that infection may be one of the components with MS.
Two other candidates that have become of particular interest to the international community over the last 5 years are Epstein-Barr virus and vitamin D.
With Epstein-Barr virus, it is a very common infection often giving glandular fever in adolescence and in fact, in most communities, over 90% of people will have antibody evidence of an Epstein-Barr virus infection by the time they reach adulthood. A meta-analysis on more than 13 MS case control studies found that people with MS have a different pattern of antibody response than other people to this Epstein-Barr virus. This is now also being shown prospectively in follow-up studies; people who have abnormal antibody levels to Epstein-Barr virus are more likely to subsequently develop MS. There is a lot of work now trying to understand the mechanism of that infection. What determines its host response? How does it affect the immune system?
The other area that is of interest is that of ultraviolet radiation exposure and vitamin D. In places like Australia, more than 90% of a person’s vitamin D is generated by contact with the sun, which is why it is sometimes known as the sunshine vitamin. Many decades ago, exposure to sunlight was proposed as one of the possible explanations why MS was so much less common near the equator, where, in the tropical regions where sunlight levels were higher. Certainly, as part of the Menzies research time we have looked at latitudinal gradient of MS in Australia in relation to UVR. There is a very strong correlation that as regional UVR goes down, then MS levels are higher. In fact, that’s higher in magnitude than the reverse – for regional UVR and malignant melanoma.
More recently, there have been studies such as the Tasmanian study where it appeared that children who had very low levels of sun exposure from ages 6-15 were at higher risk of MS. Work in the US amongst cohorts of people such as the nurses cohort, or army entrants, showing that people who had low vitamin D were more likely to subsequently develop MS. So another area of intensive interest is to try and understand how vitamin D may or may not influence the immune system, and what is the optimal level of vitamin D that people should have, particularly children, as their immune system develops.
Importance of MS Research Australia
MSRA is a very important factor in our research strategies. It is one of the major frameworks by which our collaboration continues across these 8 institutions and research institutes. That in itself has been a huge help to the value of our work; that we have had so many people of different expertise from different areas of Australia. MSRA has very much facilitated that.
Along with many international collaborative groups, we realise that the causes of MS are not going to be just a single factor. As was said before, there may be many multiple factors coming together. With the help of MS Research Australia, we have been able to improve the depth of this Ausimmune study considerably. Rather than just look at one factor by blood test, we have been able, with ethical approval and subject consent, to store blood so that we can later go on to do genetic studies, immunological studies, viral and infection studies, as well as having the environmental data. I see this as an absolutely excellent feature of this very major national Australian effort because there are some studies that just have a single infection hypothesis, or other studies elsewhere that might test a genetic hypothesis, but to actually be able, in a large group of people (more than 800 people have participated in the Ausimmune study), to be able to look at multiple factors and not just how they relate to the risk of a first de-myelinating event, but how they relate to each other, really, I think, will help us to understand some of the causal pathways that underlie disease onset.
MS Research Australia has also been very helpful with funding some follow-up work of that study, because once we establish the platform, particularly with people with a first de-myelinating event, we then had a very large baseline collection of data. With the support of MS Research Australia and other groups, we hope to look at how people progress over time. What distinguishes people who just have a one-off first de-myelinating event and never go on to develop MS, compared to people who have repeated attacks and quite a serious course? Most studies around the world recruit people at the stage of established MS, rather than this Australian project which has really tried to come in very early at first presentation to clinician. I must thank the Australasian Neurological Association for a fabulous and coordinated effort into making that possible. We hope to make the most of that over time; to really understand what influences early onset disease.
The other way that MS Research Australia has been very important is in communication with the community, because this study has had many components. It is quite complex and we really need good community participation to understand what differs between people who develop MS and people who do not. This has been an important part of the project, to have MSRA’s involvement in that community aspect as well.
The importance of the study
From the Australian community’s point of view, and there are not many diseases that affect fairly young people (the average age of onset in our Ausimmune study was people in their late 30s) where so little is known about the disease. You know that you are probably going to have a high return for research if you have a disease where, if there is knowledge, then the knowledge can lead to change. I certainly think MS is one of those diseases and in that case, very worthy for increased knowledge.
I know that many of the people with MS are very dedicated to not only improving their own environment for their own health, but for the next generation and to contribute information to that. I think that we have an obligation to try and find out what are those factors that make a difference to disease; the environmental side as well as the genetic and immunological side.
What could be achieved with further funding?
Further funding would help our work in many various ways.
For a start, we have collected extensive amounts of data and we now have to carefully analyse the data. It’s all very well having a multi-factorial approach to disease, but it means that it’s very complex statistical analysis and data analysis that is required. To get answers sooner, a funding support of that component is certainly going to help to large body of work.
The other component is that we have stored all these specimens carefully and meticulously, and some of these lab costs in themselves for different types of tests are very expensive. At the moment we would not have the funding to do some delicate immune tests and tie them in with the population based environmental data and genetic data. Yet, if we had further funding support, then it would be possible to make more of the actual resource that we have currently with the help of the Australian community, including people who’s first de-myelinating events accumulated.
The strength of Australian MS Research
I think one of the opportunities we have in Australia is that we have been able to take a national research approach to the disease. Given that the country has a lot of environmental diversity and very big differences in disease rate across different parts of the country, it makes sense that Australian research, particularly looking at environmental causes of MS will yield some information that is internationally unique. I think that is why we were funded from overseas organisations to conduct that work. I also think our collaborative teams with multi-disciplinary groups of immunologists, geneticists, epidemiologists even, sun-exposure experts and so on, over time, puts us in a very good position to try and investigate a complex multi-factorial disease like MS.
There is a lot of international scientific interest in the ongoing Australian Multiple Sclerosis research, including the epidemiology research. One example of that is that Harvard University in the US has asked us if they could pool some results from their studies, and other European studies and our studies to look a little bit more at some of the possible gene-environment interactions that are occurring in Multiple Sclerosis. For Australian research, I think that is a very positive indication that we are moving in the right direction when we have those sorts of collaborative bridges being built.