Identifying Genes Involved in Migraine for the Development of Better Diagnosis and Treatment [Interview][Transcript]

Professor_Lyn_Griffiths_migraine_genes

Guest: Professor Lyn Griffiths
Presenter: Wayne Bucklar
Guest Bio: Professor Lyn Griffiths is the Executive Director of the Institute of Health and Biomedical innovation at QUT. She is a molecular geneticist who has been studying the genes involved in common human disorders for nearly two decades.  She has published over 280 research papers, supervised 35 Postgraduates and 38 Honours students and received significant competitive grant and industry funding. Amongst her many achievements, Professor Griffiths was a Queensland Finalist for Australian of the Year in 2005 and has been awarded a Centenary Medal for Distinguished Service to Education and Medical Research. Professor Griffiths was also one of the speakers at the recent Blackmores Institute Symposium held last

Segment overview: In today’s Health Supplier Segment, we are joined by Professor Lyn Griffiths a leading Australian medical researcher who has been studying the genes involved in common human disorders for over two decades, specifically genes involved in migraines. Professor Griffiths’ Her expertise is in the field of human gene mapping and focuses on identifying the genes involved in common complex disorders, including migraine, cardiovascular disease and several types of cancer. She established the Genomics Research Centre at the Institute of Health and Biomedical Innovation at the Queensland University of Technology. The main focus of her research is aimed at identifying genes so that better forms of diagnosis and treatment can be developed.

Transcription

Health Professional Radio

Wayne Bucklar: You’re listening to Health Professional Radio with Wayne Bucklar. My guest today is Professor Lyn Griffiths, she is the Executive Director of the Institute of Health and Biomedical Innovation of QUT that’s in Queensland and she joins us today from Brisbane. Lyn welcome to Health Professional Radio.

Professor Lyn Griffiths: Oh thank you very much Wayne.

W: Now I understand Lyn that you’ve been studying genes involved in common human disorders for 20 years or so now and specifically your interest lately has been taken by genes involved in migraines.

L: Yes, I a molecular geneticist and that means that we try to undertake studies to identify genes involved in disorders. I focus on human genetic disorders and in particular on common complex ones. And by complex I mean not just tricky disorders but disorders that involve multiple genes and probably other interacting environmental factors. Probably the main area of research that my lab group is known for is our work on migraine and migraine has a strong genetic component. So we first started working on migraine in the 1990’s, then we’re one of the first groups in the world to start looking at the genetic basis of migraine. And we started to collect samples from cases and controls but also from large families so that we could try to identify DNA changes that we found in cases and not in controlled. But also that we could track from one generation to the next. So we were undertaking approaches to try and identify what genes play a role in this disorder. Now we do know it has a strong genetic component, about 90% of migraine sufferers have another close relative who suffers from the disorder. And about 50% of the time it’s a close relative – a mother or a father. So it’s a strong genetic component, but there are some well known environmental components and in fact there are specific triggers that migrainers can quite often identify. They’re usually really good things like chocolates, or red wine, or nice kisses, or coffee, sometimes there are other things like strong perfumes, or cigarette smoke, or strong lights, or even changes in stress levels. So these are considered to be the environmental triggers that operate on a genetic background. So for those that are predisposed with the genetic background, these can be the triggers that bring on the actual attack in migrainers. Now if we’re to think about migraine a little bit, would you like me to describe a bit about that?

W: Yeah, I’m curious Lyn. Does that mean that if you never had a family history of migraine, then it’s not going to occur like is the reverse true as well?

L: No, not totally. So what you find as I said a little bit a while ago was that 90% of migraine suffers have another close relative. So that does mean that 10% of people are what you’d call “sporadic” so and that varies a little bit from one population to the next. So figures thought to be somewhere between 7 and 10% with the sporadics. But most of the time you’ll find that there other family members that will also suffer from migraine. It’s actually a really common disorder as well and I don’t think people realize just how incredibly common it is. So probably the largest study in the world was undertaken in the US and this was a really careful study where they interviewed 36,000 people.

W: Wow.

L: Quite carefully to talk about their headaches. And they found that of that, 18% of women suffer from migraine, and 6% of men, and 4% of children. And it’s really, that’s a very high level. And I suppose probably the general figure would then be around about 12% of the population would suffer for migraine. Now there’s been no comparative large study in Australia, there hasn’t been any. I think the last study was in the early 90s so certainly there hasn’t been any recent studies in Australia. But we have a similar sort of population to the US and so it’s probably around about 12% of Australians would suffer from migraine as well. And in fact if you look around the world in just about every population that’s been looked at, you’ll find that the levels are pretty similar. Sometimes a little higher, sometimes it goes up to about a 20% but overall probably around about 12% in most populations. And in every population, you’ll find that 3 times more females than males suffer from the disorder. So this huge increase in female is kind of unusual that it’s so high. But the funny thing is when you look at children, it’s equal in the sexes male and female, so it’s about 4% of children. But the big change happened around about puberty where you suddenly start seeing large increase in the large number of females that suffer from migraine. And this is most likely because there’s been interacting hormonal influence that’s playing a role in that onset of the disorder in females.

W: And with those sorts of numbers Lyn, it’s got to be a big enough disease based to have an impact on gross domestic product I would think. I’m astonished at how large your figures are.

L: Absolutely right, like huge impact in terms of things like treatment, days in hospital, days of work, effect on quality of life, all sorts of effects. Probably there was an economic study again in the early 90’s in Australia and they estimated the impact would be something like 720 Million but that was on the early 90s – that’s probably gone way up now if you did one more recently. But yes, it has a huge impact on people’s individual life, on their families, on their work life, on their quality of life so, and that’s not even thinking about things like treatment and loss of productivity, days off work, all of those sorts of things and hospitalization in some cases. So it’s a very common disorder, there’s no simple diagnostics for the current common forms of migraine, simply based on how you describe your symptoms to your doctor. There are some guidelines about how you define those symptoms and how you classify migraine and the subtypes of migraine. But I think there is a real need for better tests for it, but there is also a real need for a better treatments. So there are some very good treatments and probably the most common class of treatments what’s called the “triptans.” So they tend to be directive towards the serotonin neurotransmitter levels and they work very well for probably up about 50% of migraine sufferers. So clearly there is another 50% where they’re still looking for good treatments. So some of them are useful for some people, some of them have bad adverse side effects, and some of them just aren’t useful. So there is a real need to develop some new treatments that don’t involve high levels of pain killers etc. So a more targeted approach and that’s I suppose really why we got interested in trying to identify genes and trying to develop better diagnostics and better treatment. So I’ve been involved in this, not on my own but I have a lab group with a 20 or 30 people who are focused on molecular genetics. And over the years we’ve undertaken a number of studies and been involved in identifying a number of genes that play a role in migraine. And I suppose you could classify them in 3 categories, one would be “neurotransmitter related genes,” another would be “hormone related genes” and the third one will be “blood flow related genes.” If you look at the neurotransmitter one’s, the genes that have been identified in this phase has generally been identified in the really severe types of migraine. So I think when you say about migraine you think “Okay, it’s a head pain. It’s associated with nausea and vomiting and photophobia and phonophobia.” But there are actually some very bizarre neurological symptoms that are also associated with migraine and it’s usually in the early stages of the head pain or just before the head pain. They tend to be visual disturbances, flashing lights, wavy lines, loss of vision, tunnel vision, even complete loss of vision, they can be speech defects associated with it, it could actually be paralysis of part of the body, weakness part of the body, and even extended coma. So all of those symptoms with migraine fit under a category called “migraine with aura” and that accounts for about 30% of migraine sufferers. And under that category, there is another very severe one called the “familial hemiplegic migraine” and this is where you have the paralysis and even coma can come out of it. And by studying families who have that, there’s been some studies that have implicated a number of genes that play a role in this, and one’s a calcium channel gene, one’s a sodium channel gene and another one an ATP gene and these are genes that are expressed in neural cell that can have mutations, so they’re not expressed or they don’t function normally. And this results it’s not just susceptibility, they’re causative – if you have the mutation you have it and it pass on through your family. Those are genes that you can be used then, and that information can be used for diagnosis. So we currently undertake diagnosis through all of Australia and New Zealand by investigating those genes and providing that information back to neurologists, clinicians, and hospitals. And they can then provide that information to the patients and start to look at what’s the appropriate treatment or differentiate the diagnosis from other similar looking disorders, sometimes which look like stroke or ataxia or other cardiovascular typed disorders. So it’s good for diagnosis and it’s good for actually picking the treatment in some cases as well. We’ve also identified a potassium channel gene and again in neuronal one, and this is in the more common type of migraine with aura, without a paralysis or the coma but it’s again a mutation. And we’ve also identified in the second category a role for hormonal related genes, variations in the estrogen and the progesterone receptor which seems to play a role in a subtype of migraine called “menstrual migraine” so it relates to the hormonal fluctuations bringing on the migraine attack in some females who have that. And probably the last one I’ll mention is the blood flow one. And that’s I’d say that what I think is the most interesting one, from our point of view. And from this one it’s a fairly common gene mutation in the gene called it’s a long name methylenetetrahydrofolate reductase MTHFR. And this gene is involved in a folate pathway, it has a mutation in it that results in about half the level of the gene product which is an enzyme being produced. It’s been associated with a number of different disorders but in particular cardiovascular ones in stroke in particular. We tested it in migraine a number of years ago and we found that this mutation occurs much more often in people who suffer from migraine with aura than normal people. Many other studies around the world have replicated this so largest one of about 3,000 migraine people showed that it really is a susceptibility gene for migraine. And so if you have that mutation, you’re much more likely to suffer from migraine with aura. You’re also at higher risk for stroke, it doesn’t mean you get it but you’re much more likely. And we think that that gene plays a role in that morbidity. But the interesting thing is that in the 1980’s, this enzyme MTHFR have been studied really well and they’ve been able to study the co-factors for the enzyme and worked at how it works, what makes it work faster, what made it work slower, and what the pathway looks like. And so from those studies has showed that a cofactors are in fact a certain combination of B-group vitamins – quite specific ones. And so we thought “Well okay, if people who suffer from migraine with aura and have this mutation they have half of the level of enzymes that they should have, it results in high level of particular chemical called “homocysteine” which puts them also at an increased risk of stroke and other disorders.” We thought well what happened if we add more of these co-factors if we add some more of this vitamins to those people, would it drop that homocysteine down to normal level by making the enzyme work faster? So we undertook a trial, so a double-blind placebo controlled trial, where we did exactly that. And we gave people a specific combination of 3 different B group vitamins to make the enzyme work faster. And then we followed them over 6 months, and it what was placebo controlled and blinded. And what we showed at the end of that was actually a really interesting thing, that we were able to drop that homocysteine level down to normal, make the enzyme work faster, dropped the homocysteine level down to normal in those who have the vitamins. Those who run the placebo we didn’t do that. More importantly it drop the frequency, their severity and the pain of their migraine, only in those on the treatment. Now that was a trial of 52 people, we then did another one of 250 people and we did another one recently 400 people. And in every case we found the same thing, that even if you had the mutation, this particular combination of vitamins could overcome it and could make your homocysteine levels go down to normal. But more importantly it could have a significant effect on your migraine severity and pain and disability. So we think for some people at least, it could be a useful preventive.

W: Yes. And it does sound like one of those very safe interventions. It’s kind of worth it even if it’s not guaranteed.

L: Well being a vitamin, it’s actually a useful thing. So yeah, it tends to be safe and relatively inexpensive. It’s still a kind of specific combination and it’s a high level of one of those b-vitamins too so you won’t kind of easily find it by eating sort of a whole lot, or eat anything. So it is specific combination, but we actually think for some people it could be really useful sort of additive to their kind of regimen of how to deal with their migraine. It doesn’t totally stop them and you certainly need, when you do get one you don’t need to take your medication whatever’s appropriate to you.

W: Yeah.

L: But it’s a good preventive in that it reduces how often, how long, and how severe you get that. So I think it would be useful.

W: You’re listening to Health Professional Radio. And I’ve been in conversation with Professor Lyn Griffiths, Executive Director of the Institute of Health and Biomedical Innovation of QUT. And we’ve been involved in a fascinating chat about “genetics and migraine,” so I guess to summarize very closely. Lyn time has beaten us but before we go, my favorite question in every interview is about misconceptions. What’s the biggest misconception about your work amongst your colleagues, clients, patients, that drive you nuts and keep you awake at night? Maybe we could help disperse it a little.

l: Well I don’t know if it’s a misconception. But I do feel obviously my passion is to try and identify genes for disorder and to translate it for better diagnosis and treatment. But I do feel that a lot of people don’t take migraine seriously. That unless you actually suffer from it or someone that’s close to you suffers from it, and you don’t seem to think it really is a big issue. However for some people it’s an enormous issue, and as I mentioned it’s a really common disorder. It can be incredibly disabling for some people, and it can really affect their life. I mean, by definition migraines last between 4 and 72 hours. Now 72 hours of a severely disabling head pain where you can’t actually do anything, where you’re very nauseous and vomiting or even some cases were you’re hospitalized. That’s episodic too, it doesn’t just happen sort of once every 10 years, it can happen quite regularly. I think this is an enormous impact on someone’s life. And one of the things that bothers me is that I suppose people don’t seem to think of it as a serious disorder. I think sometimes if you say you have a migraine, people think “Oh you just had a big night out on Friday. What were you doing, was it a good party?” or something that in a lot of cases, it’s not. It’s a disabling and very common disorder, I think it’s a 7th most common disabling disorder in the world. It’s one of the big top 10 sort of one’s that affect people and yet it doesn’t kind a have the name, or some other areas and I don’t think it has the emphasis on research or emphasis on making difference, a change that’s gonna impact on people’s lives. So yeah, I think the thing that worries me is it doesn’t seem to sort of a say “serious disorder.”

W: Well certainly today we can help with the people who have migraines because they absolutely know it’s a serious disorder already. But maybe we can dispel that a little bit amongst the people that don’t have migraines. And I absolutely agree with you, that it is for those people who have them a very serious and debilitating disorder. Lyn it’s been a pleasure having this chat with you today, I do always enjoy chatting with academics – we regularly talk with the health academy. But the beauty of talking to someone like you is that this is your passion and you absolutely know it inside and out and you’re able to make it understandable for us – people who are not quite so up to date with what’s happening so thank you for your time and patience.

L: Oh thank you very much Wayne. It was a pleasure talking to you.

W: Now the good news is if you’ve just missed my conversation with Professor Lyn Griffiths the Executive Director of the Institute of Health and Biomedical Innovation at QUT, then you’ve missed a fabulous interview of her. If you have any interest at all in genetics or migraines, please head off to our website, we have a transcript, have a read. We also have an archives of the interview so you can listen to our whole interview again on both YouTube and SoundCloud. You’re listening to Health Professional Radio, my name is Wayne Bucklar.