Genetics and MS

Jodi: Hi everyone. Welcome to our webinar today on genetics and epigenetics in, in Multiple sclerosis. A very challenging topic for someone to describe. And having been an MS nurse for a long time now, I've never been able to truly be, find the right words to explain the genetics and the epigenetics and what those terms actually mean. So, what I did is call upon a colleague, Dr. Vicki Malley to come and present to us.

So in a spirit of reconciliation, MS plus acknowledges the traditional custodians of the country throughout Australia and their connections to land, sea, and community. We pay our respects to their elders past and present and extend that respect to all Aboriginal and Torres Strait Islanders people today.

Vicki has completed her PhD in Molecular Epigenetics at the University of British Columbia in Canada. She moved to Newcastle, and she is now the manager of the MS Research Group at John Hunter Hospital. They do have a special interest in MS genetics and have been working in that area for a long time and really producing some really good understandings of the role of genetics plays in MS. Vicki's research focus is on epigenetics and the factors that involved in multiple sclerosis, and she's working on genome-wide epigenetic changes in various immune cells in MS. So, she's going to be able to explain all of that a lot better than what I do. So, what I will do now is we will start to play Vicki's webinar.

Thanks for joining us Vicki and I am really looking forward to hearing all more about genetics and epigenetics. I'll hand it over to you.

Vicki: Thank you, Jodi. Thanks for the invitation today to talk about genetics and epigenetics and MS.

So, what do we mean when we say genetics? Let's start with a bit of a background. So, genetics is the study of genes. It's also the study of genetic variation between individuals, so different versions of each of the genes. And it's also the study of how traits, so for example eye colour, are passed down from one generation to the next. So, we're at a point now in research where we can relatively easily study all the genes in an individual at once which we collectively refer to as the genome. So, some of you may remember back in 2003 because it did make mainstream headline news the completion of the Human Genome Project. So, this was a huge international effort that took 13 years. But it was a really pivotal point in genetic research because we now have a reference genome to go back to.

So, when we're looking at different diseases, we have a reference to go back to see what the differences between people affected with disease and people not affected with disease are.

So, to understand genetics I like to use the analogy of a cookbook. So, your genome, which is all of your genes all of your DNA, is like a cookbook, and it's a cookbook that tells you how to create a human. And the genes are the instructions that each cell in your body uses to function. So, we have our cookbook, which is our entire genome, so this is all of our DNA, it gets split up into individual chapters, so just like your cookbook might be divided into sections for, say, breakfast, lunch, dinner, and dessert, your genomes also split up into little segments of individual chapters, and we call these chromosomes.

And finally, within those chapters you have genes, so these are individual recipes for individual dishes, although in the case of your genome, each gene codes for an individual protein. So, if we look at your genome, or the cookbook, your genome, if you lined up all of your DNA, it would be like a very fine two meter long thread, and this is what you can see over the right hand side here. So that top structure is what we call the double helix. And this is how your DNA is structured in your genome. So, most of the cells in your body have the same DNA. And this DNA is made up of combinations of four different structures, which we call base pairs. And these are referred to as, so that's adenine and thymine, which we just call A and T, and guanidine and cytosine. So, these are G and C. They're like the letters that make up the words of all the instructions that the cells read. So, your chromosomes are the individual chapters. So, your two meters of DNA, if you had to read that all at once, it would be quite a long fragment. So, it's split up into nice little segments, which we call chromosomes, and they help just keep your DNA organized, like the chapters of a book would.

So, if you think about the chapters of your book or your DNA without chromosomes, it would look a bit like this picture on the left here. You're never going to find the recipes you want in that pile of mess. But when you put it into chromosomes, it's like putting it into a nice binder, like you can see on the right here, where it's all nice and tabulated. You can easily find the recipe that you want from the section that you want. So, this is the primary functions of the chromosomes.

And you have 23 pairs of these in total, so 46 altogether. And at certain points in the cell cycle you can actually see these chromosomes under a microscope, and they look a little bit like the picture that's on the left here, so that's a microscope view of the chromosome. And what we know is that you get one of these from your mom and one of them from your dad. So, if you look at the pairings, for example, that chromosome one there, you can see there's a banding pattern, but it is slightly different between the two chromosome pairs. And that's because one's from your mom and one's from your dad.

So, they have the same information. They're just a little bit different in terms of what genetic material they carry. Now, 22 pairs of these are exactly the same between males and females. And the 23rd pair is what we call the sex chromosomes. So, if you have two X chromosomes, you're a genetic female, and if you have an X and a Y, they still make up that 23rd pair, but you are a genetic male.

Now, this is the part we're going to talk about today. So, these are the individual recipes or the genes. So, if you remember, if you go back to our analogy here the chromosome is the structure that's organized your DNA, and then there's that long string of DNA that comes off it. And there in that little pink section, you can just see one little segment you can see one little segment of the DNA, and that's the individual gene. And humans are thought to have somewhere in and around 20, 000 genes altogether. And these genes each code for traits, for example, eye colour or hair colour, or in some cases, diseases.

So, when we're talking about inheritance, genes are the basic unit that are passed down from one parent to the offspring, or from both parents to your offspring. The passing down of traits from parents to offspring is what we actually refer to as inheritance, and we inherit different versions of genes from each of our parents.

So just to give you an idea of the types of genetic variation that can happen, and keeping in mind that not all genetic variation is bad. Some of it actually doesn't make any difference to you whatsoever and you would never know that you had a genetic variation. Some of it is bad and can cause disease, but some of it might also provide a selective advantage. So, it makes you a bit better than other than you otherwise would be than a so called normal version of the gene.

So, here's our example, we're going to use words as an example. So, the normal word is the word BEAST. So if we want to do a substitution type change, we just change one letter and our BEAST becomes a FEAST. Now if we want to do a different type of variation, it's called an insertion, we add one letter, so in this case we've added the R, and our BEAST has become a BREAST. And the opposite of that, we can also take away a letter, so in this case we've taken away the A, and we now have the BEST. And finally, there's a different type of mutation called an inversion. And so, this is where transcripts two letters will swap around with each other. So, in this case, the S and the T have changed positions, and we have BEATS.

So, something that's important to note is not all of this happens at a single nucleotide level or a single letter level. It can happen to large sections of the genome, or it can happen, as we've seen here, as just as a single letter. And today for MS we're mostly going to look at variations that are substitutions.

Now, as I said we are calling them variations, and rather than mutations, which is what most people think of. And I think because we don't, we call them variants rather than mutants, because I think that people hear mutants, and they think something along these lines. So, they think of the X Men, which is maybe good, maybe bad, depending on who you are. But we don't really refer to them as mutations anymore. We do just call them variants as an acknowledgement that sometimes they make no change whatsoever. Even though sometimes they may have an advantage or a disadvantage.

So how can variants be passed down through different generations? So there's two main ones. One is a dominant variant and this is where we only need one copy to show the trait. But there's also a recessive variant, and in this case, you need two copies in order to show the trait. So, the easiest way to explain this is with eye colours.

So, in this case with brown eyes, you could have inherited one brown eye gene from your mum and one brown eye gene from your dad. Or you could also have a brown eye gene from your mom and a blue eye gene from your dad. In both of these cases, you end up with a brown eye because the brown eye gene is hiding the blue eye gene, its blue eye is recessive to the brown eye. But you still have the brown eye trait. However, this person with brown eyes is called a carrier for the blue eye trait.

So, when we think about this in terms of genetic disorders, both parents could be completely normal and have no signs or symptoms of a disease, but their children could still end up with that disease and end up with the symptoms of the disease because both their parents were carriers. So, they were hiding the actual trait, but they passed, they both passed that trait on to their offspring.

So, in the case of recessive traits, you actually need two copies in order to see the trait in the population. So, the example is blue eyes here. So blue eyes was a recessive is what we call, or not dominant to other eye color traits. So, you would have need to receive a blue eye gene from your mom and a blue eye gene from your dad. In this case, the blue eye gene has nothing to hide behind, so there's no dominant eye color to hide behind, and the individual actually has blue eyes.

So, this means that recessive traits and this would be the same for diseases that are carried on recessive genes, are less common or more rare than dominant traits so depending on where you look on the internet, and I won't pretend to be an expert on eye colour, I've got very different responses, depending on which Google page I looked, but allegedly blue eye colour is only about 8 percent of the worldwide population compared to brown eye which is about 80 percent of the population.

So, there are other ways to pass variants down through generations. So, one of them is X linked. These are variations that are carried on your X chromosome. Now men are more likely to show this trait because they only have one copy of the X chromosome, so they don't have a second copy to hide behind. So regardless of whether or not the trait is dominant or recessive they will still show this trait. So, a great example is red-green color blindness which is X linked and is more common in men than it is in women. You would need two copies of the colour-blindness gene in order to be red-green colourblind.

And you can also inherit traits through mitochondrial inheritance, and this comes exclusively from your mum but we're not going to talk about those today because it's not the type of genetics we're going to talk about in regards to MS.

So, what does all of this mean for your MS, and what do several decades of genetic studies tell us about MS?

So, first of all, we know that you can inherit MS, so a family history does make you more likely to develop MS, but it's not considered a true heritable disease. So truly heritable genetic disorders are inherited from parents by their offspring in a predictable manner. So, if you think about the dominant, recessive, and X linked patterns that I talked about earlier, this doesn't happen in MS.

The good news about that is that if you have MS, it doesn't necessarily mean you're going to pass it on to your children or your grandchildren. The bad news about this, it means you don't necessarily need a family history of MS in order to get MS.

So, how likely is it that you will develop MS? So, in the general population MS is at a rate of about 1% one person in a thousand. But this really depends on where you live. So, if you live in northern European countries or if you have a racial background that's northern European descent, you have a higher risk than someone who lives closer to the equator or is descended from a racial background that's closer to the equator.

If you have a family history, this risk increases. So, in all of these slides, we'll say that you are this green person, and your affected family member is the person that's in red. So, if you have a first degree relative, so these are people immediately related to you so one parent with MS, your risk is 1 in 50. If both of your parents have MS, your risk goes way up, and it's 1 in 8. If you have a sibling with MS, your risk is about 1 in 20 of developing MS. Now if you have a second degree relative, so these are people who are one further step removed from you, such as grandparents, an aunt or an uncle, or a first cousin, the risk of developing MS is about 1 in 100.

Now this is the really interesting one. So, if you, again, the person in green, have an identical twin with MS, so you share the exact same DNA sequences, your risk is still only about 1 in 3. So, the reason this is really interesting is because it shows that while there is a genetic link to MS, just because you have an MS related gene doesn't destine you to MS.

So, which genes do you need to worry about in particular? So, there's been several collaborative projects that have been done worldwide by a lot of different MS researchers and contributors, and they've identified over 200 genes that are thought to be linked to MS. to the risk of developing MS. And I think the last time I checked that number was around 233.

Most of these genes are involved in some sort of immune system function. So, they're genes that are related to your immune cells. Some are also linked to other autoimmune diseases, which makes us think that maybe those genetic variants are more linked to autoimmune disease in general and less specifically to MS. The strongest link has been known actually since the 1970s, so we've known this for quite a long time, and it's a gene called (HLA) DRB1*1501. And the 1501 simply refers to the MS variant of that gene. And it's a substitution type change. So, if we remember back to our analogy, it's the one where we've simply changed one letter.

And if you have the MS risk variant you are three times more likely to develop MS, than someone who doesn't have it. And there is a protective variant, it's called HLAA, which can neutralize some of the risk. I won't go too much into that today, but I do mention it a bit later on when I talk about environmental factors. So, I wanted to mention it here.

So, how about progression? Is there a genetic link to people who have severe disease versus people who don't? So, not everyone is affected by MS in the same way. Some people will see disability progression very quickly, while others don't see hardly any disability progression at all and the interesting thing is just because you have a family member with progressive MS doesn't necessarily mean that it will also happen to you.

So Last year there was two large group collaborative groups that published two separate studies. So, the first one was the International Multiple Sclerosis Genetics Consortium, and that is a bit of a mouthful, so we call it the IMSGC As well as the Multiple MS Consortium. Both of these are based in Europe, but they do have a lot of Australian contributors.

The other large collaborative group was MS Base, so that's based here in Australia. But it has lots of worldwide contributors. And both of these groups looked at thousands or tens of thousands of genomes with from people with MS, as well as healthy controls. And they found some variants that are linked to progression.

So, in the first instance, this is the group that IMSGC and multiple MS. And what we're looking at here is different variants and in people in MS compared to controls. And you can see there's a dotted line across the bottom there. So, all the little dots that are above the black spotted line are ones that are different in MS compared to controls. And the ones below are the ones where there's not really any difference between people with MS and people without MS. So, on the left hand side there is the variants that are involved in MS risk, and as we expect, if you look at the blue dots and the little legend on the left, they're mostly involved in immunity.

So, we already knew that, so that wasn't super exciting. What was interesting is the panel on the right, where most of the little dots that fall above that black spotted line are orange, and these are genes involved in the central nervous system. So, these are involved in nervous system function. So, what this tells us is that if you have variants in your immune related genes, you might be more susceptible to developing MS in the first place. But if there's variants that are involved in the nervous system function, these might be put you more at risk of developing progressive MS.

Now the group here in Australia, the MS based group they did a similar study, but they had a slightly different approach to this. So, what they did was they looked at EDSS scores or disability scores over a very long period of time. So, some people had up to 40 years’ worth of disability scores accumulated on the database. And what they did was they classified people as either having severe disease, so this was very rapid disability accumulation, or very mild disease, so this was very little disability accumulation over the years.

And what they found was that there is also no link to genes in the immune system when you're comparing people with severe disease versus mild disease. But what was really interesting was that they were able to use those genetic differences to predict whether someone was going to have severe versus mild disease over a long period of time. So, this study was a bit smaller than the IMSGC multiple MS cohort, so it does require further investigation before we can really make those calls and make those predictions. But what was unanimous between both the groups was that genes involved in nervous symptom system function are more related to disability progression but even those genes had very little heritability. So this was only 13 to 20 percent. So, this was really quite low still.

So what? So, what does any of this mean? So, we know that there's lots of genes that put you at risk of developing MS. We know that in terms of developing MS, they're immune system related, but we know that there's also genes that put you at risk of progressive MS. So, you might be thinking to yourself, but Vicki, you’ve just told us that none of them have much heritability. They don't really increase my risk very much. So, what is the point of doing all these genetic studies? So, we now have different ways of actually analyzing genetic data. And one of these is using polygenic risk scores. So, this comes from our ability to look at a lot of genes or whole genomes relatively easily now. And I think this may be the future of actually predicting disease risk and disease outcomes.

So polygenic risk score, even though it sounds like a big scary word, is really just a number that is created by combining all of the different genetic variations that you have. And we call this a score, and it lets us assess risk of any given disease or outcome based on risk information from your whole genome. And this is now being done for people with MS. And what you can see, and I don't expect anyone to have to read too much into this, but the orange peak is people with MS and the blue peak there is people without MS. And the Risk score is the line at the bottom. And so, what you can see is people with MS, when we look at all of their genes together, they have an increased risk score compared to people without MS. So, this is a really good way to look at a lot of different genetic information and especially when it relates to complex genetic diseases like MS, where there's not one single golden gene that's going to tell us the answer.

So, you may also recall back a few slides that I talked about Northern Europeans having a higher risk than everyone else. Now you can see that on this map here, so the darker the red color, the higher the prevalence of MS in that region, and you can kind of see that through the middle of the world there, it's pretty pale, and at the ends at either end, closer to the polar regions the risk is a bit higher. So, originally, this was assumed that it was a latitudinal gradient and that the farther away from the equator you were, the more likely you were to have MS. And it was postulated that this might be related to vitamin D levels. So, people who were further from the equator got less sunlight, therefore had lower vitamin D, and therefore had more MS.

But we've recently found out that vitamin D supplements don't actually prevent you from getting MS. So, the question is, why not? And in January this year a group from Cambridge and authored by Barry and colleagues they have postulated a new hypothesis. So, this has just come out in January of this year, and what they did was they took DNA samples that they extracted from the teeth and the bones of people who lived during the Mesolithic and Bronze Age period. So, this is five to ten thousand years ago, and they compared them to people who lived slightly more recently, so about two thousand years ago, as well as from modern DNA from the UK, MS bank. So, during those two periods, the 5 to 10,000 years ago, there was a group of people called the Yamnaya people. I think that's how you pronounce it. I'm not an expert on this particular subject, but this is when the Yamnaya people moved across Western Europe and as they did that they flourished. So, they passed on their genetic information to pretty much everyone that they came in contact to. And they'd originally come from the steppe region, which is modern day Ukraine and Russia. And they spread all over Western Europe, as you can see here on this map. And so, they were herders. So, they were nomadic herders. And so, they took sheep and cows and they herded them around. And as they moved through Europe, they brought more of the farming herding lifestyle and slowly the more traditional hunter gatherer lifestyle phased out and the farming lifestyle came in.

And they were thought to be the original carriers of the HLA DRB1 MS risk allele. Now why would this have a selective advantage? So, as they moved around, they brought pastoral practices. So, this is animal herding, and this farming put humans into closer contact with animals like sheep and cows. And this variant may have heightened the immune system, which would have protected them from infections that may have arisen from animal to human contact. So, these are zoonotic infections. So, this is the. The hypothesis that this group has put forward and so, of course, in a day and age, five, ten thousand years ago, where there was no antibiotics, no antiviral therapies, no modern medicine having an advantage where you were less susceptible to infections and infectious diseases would have actually been an advantage. So unfortunately, it also increased the amount of that MS risk allele and made Northern Europe a bit of a hotspot for disease.

So, this is by no means, I don't think will replace the latitudinal gradient to the vitamin D hypothesis. But it certainly adds another option and another hypothesis going forward. And there's definitely some more work to be done here to try and show that that is actually what's happening.

So, what have we learned so far? So, genetics is the study of genes and heritability. MS is heritable, but not in a traditional manner. There are a lot of genes that are linked to developing MS, but none of them result in a very high risk. MS progression, which is also got some genetic links although it's also not particularly heritable, but combining all the genetic information together and creating these polygenic risk scores might help us better understand the risk of disease and progression. But those identical twins with identical DNA still don't always both get MS. So, what else could be going on?

So, we know that environment also impacts MS its risk and its progression. And the ones that are probably the best studied are smoking the latitudinal gradient, which I just spoke about, and also EBV and other viruses. So, I won't go too much into this, but last year there was a big paper published on EBV and the risk of developing MS, and this has been a long standing debate. So, this is Epstein Barr virus. It's the virus that causes glandular fever, or mono. And Almost everyone with MS has been infected with EBV at some point, but everyone without, almost everyone without MS, has also been infected with EBV at some point. And so, this has always led to more questions than answers. Is it the timing of infection? Is it whether or not you were sick with glandular fever or if you were asymptomatic? And so, it's been hotly debated for a long time.

There was a large study last year that was published early in the year, out of Harvard, and what they did was they had blood samples from 10 million young people on military duty. And during their military duty in the US, 955 of them were diagnosed with MS during active service. And they also had yearly blood samples from these people. And so, what they did was they looked at their blood samples and they could time when they were infected with EBV during their military service and when they developed their MS. And what they found was that MS symptoms came about roughly five years after their first EBV infection. And that EBV infection made people 32 times more likely to develop MS than people who were never infected with EBV. So this is a really strong correlation between EBV and MS onset. And they were also able to correlate it with a marker for neurodegeneration, which is called serum neurofilaments, but we won't talk too much about that today.

So, the other environmental exposure that's well studied with MS is smoking. Now with this plot here, I only want to point out three little spots. So, in the bottom left hand corner, there's a very flat little blue spot. Now, this represents a person who does not have the MS risk variant, but they do have the protective variant, and they have never smoked. If you go all the way to the right hand side of that plot, there's a slightly taller blue spot. And this is a person who does have the MS risk variant. They do not have the protective variant, but they're still not a smoker. So, you can see their risk has gone up by maybe double, maybe three times. Now if you go to the back of this plot, there's a really tall purple column. And this is someone who has the MS risk variant. They do not have the protective variant and they are a smoker. So, this is a 15 times higher risk of this person developing MS than a person with the same MS risk genetic background.

So, the question is how do these environmental factors like EBV and smoking actually combine with your genetics or work with your genetics to increase your MS risk? And here in Newcastle, we think the answer to this is epigenetics. So, epigenetics are a way that environment and lifestyle factors can possibly influence the genome without actually changing your genetics. So, if we remember back to our analogy where your DNA is your cookbook, your chromosomes are the individual chapters, and your genes are the individual recipes, your epigenetics is the way. The words in those recipes are punctuated so they are able to change the way your cell interprets the words and the instructions without actually changing the words or instructions themselves. So, the best way to think of that is if we take this sentence here, which is "woman without her man is nothing."

If we punctuate it this way, it says "woman, without her man, is nothing", implying that woman's nothing without man. But we can change that punctuation and we say, "woman! Without her, man is nothing." And so, you can see in this sentence, it's taken on the exact opposite meaning. I haven't changed the words, I haven't changed the order of the words, I've just changed the way they're punctuated.

And this is how epigenetics acts for your genome. It just changes the way your cell interprets what's already there, without changing the information itself. So, the fancy way of saying this is that it's a mechanism that changes the way our DNA is interpreted by the cell without changing the genetic information.

And we know that epigenetics can be influenced by environmental factors, so smoking and EBV infection definitely influenced the genetic patterns. But happily, these are also reversible to some extent, so it makes them a possible target for future therapies. And DNA methylation is the one that is the best studied, and it's the one that I'm going to talk about today, because it's the one that we do the most work on here in Newcastle. And all DNA methylation is, is a little tiny chemical that's added onto your DNA. So, we're going back here, so we remember our chromosome, which has a long string of DNA that's all wound up and organized in that lovely chromosome. If you look at the individual strand level, you can see there's little yellow dots that have been added in this pictogram, and this just represents the DNA methylation. So, it's just a tiny chemical addition to the DNA that can change the way the cell reads what information is there.

But how can this help us understand MS? So, one of the ways we think might happen is it might be able to help us show response to treatment. So, epigenetics can be studied in a genome wide manner, just like our genetics can, so we can look across the entire genome at epigenetics, and we refer to this as our epigenome. And we can, like we do with the polygenic risk scores that look at all of your genetic makeup, we can do the same thing with methylation. So, we call them a methylation treatment score or a methylation risk score. And we can use this to tell the difference between people who have taken a treatment and people who haven't.

So, this was one of our original studies, where we had a group of people who had used interferon beta. So, this is your beta, Interferon, Avanix, Rebif etc. And we were able to see a big difference, so the orange ones on the right are the ones who'd taken treatment and the blue on the left were the ones who hadn't taken treatment. And we were able to pick who'd been on treatment and who hadn't based on their methylation risk score.

More interestingly we have a long term study going here in Newcastle where we're following people who've taken Mavenclad treatment. And what we did was we looked at their epigenome right before they started treatment and we looked to see if we could split people up between those who responded well and remain stable on Mavenclad treatment and those who didn't respond. And so, this is after 3 years of follow up and what we found is that we can use the methylation risk score to tell the difference between people who had relapses while taking Mavenclad and those who hadn't.

So, this is really interesting because this was blood samples that were taken before the treatment was started and so the goal here is to look at other treatments as well. Maybe there's a way before you start treatment, we can look at your methylation risk score and tell you which treatment is going to be best for you. So that, that's the ultimate goal of this particular research project.

So, we can also detect biological aging with epigenetics. So aging, as we know, results in changes to the immune system. That shouldn't be a surprise to anyone. Everyone knows that their grandmother gets much sicker with a cold than everybody else. Aging is also a risk factor for many other diseases, like cancers. And the immune system just doesn't function very well anymore. There's an increased risk of infection, but there's also more instances of autoimmune disease with aging. And so, we wanted to ask ourselves maybe people with MS have more rapid aging of their immune system than people without MS, and maybe that's part of the reason why they've developed this autoimmune disease.

And we can use epigenetics to show how biologically old you are. So, if we look at this graph on the right here you can see there's three blue men with canes lined up on top of each other. So, the one in the middle is someone whose epigenetic age is the same as their actual age. So that means their biological age is matched up with their chronological age. The one at the bottom is someone who, he looks like he's 70 years old, but his biological age is much younger, so he's thrown his cane up in the air, and he said, ha, I'm biologically younger than I should be. And the one at the top, as you can see, so he's someone who is a very old epigenome, so maybe he's a 70 year old that has the biological age of a 90 year old. So, there's algorithms that we can use, and we create, again, a number, we call it epigenetic age acceleration. So, this is someone who's been biological age appears older than their chronological age and as assessed by their epigenome.

So, we published on this last, late last year and what we found was that people with MS do actually appear older in terms of their epigenetic age than people without MS. So the graph on the left there in light grey is cases and in dark grey is controls. And what we found was people with MS appear to be about nine months older than people without MS. But interestingly, when we looked at the immune cells in the blood, we looked at B cells. Now, these are the ones that produce antibodies in response to vaccine and infections. And in particular, the B cells appear to be five years older in people with MS than people without MS. So, there's something about the B cells being biologically older or epigenetically older that maybe contributes to MS. We also found that this is more prominent in men. So, men seem to, regardless of whether they have MS seem to be epigenetically older than women. But it's even worse for men with MS.

So, what have we learned today? So, we've learned that MS genetics is complicated. There's no single golden gene that means that you are going to get MS. There's also not a golden gene that's going to tell you what your disability progression is going to look like over time. The combined genetic risk scores may in the future improve this. So, while there may be no golden gene, maybe there's a golden risk score. Epigenetics is another way that we can use to study MS risk. But more importantly, it may actually help us predict response to treatment, and it also may help us better understand the causes of MS by showing us new pathways that are involved in MS risk.

So, with that today I spoke a lot about research that I was not a part of, but I also spoke about research that I am a part of. So, this is the team here in Newcastle. They all contribute to the, all the research we do and wouldn't be a talk if I didn't thank them for all their support over the years.

So, thank you for having me.

Jodi: Thanks Vicki. I have listened to lots of presentations about genetics and every time I do, I listen, I understand more, and I learn more. So, thank you.

In the epigenetics, one thing I was asking is, are there ways that you can change a lifestyle that might influence those epigenetics.

Vicki: So, theoretically, yes, but no one has actually proven this. So, this is one of the things we're hoping to do a diet study because I think diet is something that is important. Well, according to our consumer group, diet in MS is something people with MS are quite interested in. And so, we would like to see if changing your lifestyle, like your dietary intake, more vegetables, less fats can actually reverse that epigenetics related to MS. I don't think anybody has actually shown that conclusively.

Jodi: Okay, so we've got a while, a while away to go. Do you think, maybe not in our time, but can you see a time where people will be able to have that genetic score done to be able to help them predict, for families of people who do have MS for instance, to predict, Whether they're at risk or not?

Vicki: Yeah, I think we can. So, sequencing technology and like, the analysis of it has come a very long way especially in the last little while. So, there is, like, basically pocket sequencers now that you can just hook up to your laptop and run a sequence in 24 hours. So, and then the companies are getting wise to the fact that clinicians are never going to use those sequencers if they don't know how to analyze the data. So, they've, they've also come up with some really good analysis platforms where you basically, you just, you know, put your DNA in and tick the boxes of what answers you want, and it spits the answers out the other side. So, I do think that will come definitely. Yeah.

Jodi: Yeah. Well, it's very exciting, and I'm sure that those, those are all very exciting things to come, so thank you again. I'm sure that I'll It was great to have you and I'm sure I'll be asking you lots of questions in the future.

One of the things that did come through in the questions were around testing for children and children with brothers and sisters with MS or children with parents with MS or also questions around identical twins and what we do.

It's actually quite a complicated question. As Vicki discussed there's no particular genetic sequencing or testing that is available now to be able to determine genetic risk. When we had that question asked to us in clinic there by parents, which is a very frequent question about whether we should be doing regular MRI. Is there anything that we can do? Most of the time we said that it is still a very low risk from one family member to another family member. And so it does depend a little bit on the, the child and the person that you are thinking about when you're thinking about that, what that's going to mean for the child and what that's going to mean, how much anxiety that's going to create for them what that's going to mean to the future, considering that there still is very low risk.

So, in clinic we didn't generally recommend it. I've never looked after identical twins. I didn't have that situation. Vicki, when she answered that question, because someone asked the question about should identical twins have regular scanning? Again, she said that's really, it is for a clinician, she's a researcher, and it is for a clinician to answer. She was saying that it was sensible if they had neurological symptoms to certainly see a GP. But it is One of those questions that really needs a holistic perspective on what the cost of that's going to be in terms of that person that you're just you're talking about and also what that's going to mean for what comes after the testing as well too. So, it's a really big discussion and one you really need to have thinking about. There's no right or wrong answer to that. And there were even some sisters and brothers who we had, who we did have in clinics, say we had two members of family in clinic who had MS. We were very quick, to make sure that we scanned anyone else in the family who had some neurological symptoms that they were concerned about and then occasionally there was a family member who did want to have every couple of years have a scan and felt that they were ready to, Medicare isn't reimbursed for that, so they were happy to pay for it.

So, there's a whole lot of things that you have to put into that discussion and no real or right or wrong answer to that. Currently, good to hear Vicki again reinforce that we hopefully in the future will have a better genetic screening available that will help better understand risk.

The other question, I'm interested in the genetic susceptibility of the next generation and whether there was anything to done to minimize risk. We discussed that one. That that's very difficult because that gen genetic abnormality may or may not necessarily mean that people are going on to develop MS because it's not exactly, it's not a highly heritable disease.

Another question was, are you looking at polymorphisms such as M-T-H-F-R gene that may affect methylation cycles and could have downstream effects? Vicki said, for my work, we are not specifically looking at the M-T-H-F-R gene. When we are working on a whole genome variation, we look for genes that reach what we call significance threshold. This means that the genetic variation must have a strong enough effect or be in enough people to have statistical meaning. These are not necessarily all the genetic variations that cause MS, but by using this method we are more likely to find answers around the genetic basis of MS.

The question, Italy is not in northern European, but it's a high prevalence of MS. Do we know why? The question that we put to Vicki was, is it true where you where you've lived particularly in the first 12 years of your life can have an impact on you getting MS? Vicki's response to that was, not as much as we once thought. There used to be a strong longitudinal a latitudinal gradient associated with MS, where people nearer the polar regions had a higher incidence of MS than those who lived near the equator. However, the most recent incidents and prevalence studies show that this is not quite as strong as we once thought, and there's likely to be lots of different factors available, and that may be why, because you correct that person in, there is, there is a relatively high incidence of MS. prevalence in Italy, and there's certainly more and more anomalies over time that help build that picture of why we see increasing incidences in different countries.

And even that most recent study that Vicki talked about, the paper that was published, again, sort of indicates that perhaps it's not, the whole latitudinal gradient thing is not the whole picture and there could be more to that. And as we see more diseases emerge and we see closer links to lifestyle related to diseases, then I think that that picture may change slightly as well too.

So, it's what those factors are yet is not clear. Vicki's written, it's tempting to speculate on this being due to genetic mixing now that it's so much easier to go around the world and live wherever you want to and have children with whoever you want. But there is no solid evidence to support this at the moment. So, I think that's just you know, it's a temptation that we all want to develop but that may be explaining why Italy still has a relatively high incidence and Italy is part of Europe. So, I guess that's sort of, if you look downstream from that you can see that still closer to the equator, you're still less likely to have MS. And there's still much less incidence, for instance, in Japan than there is in Australia. And still more in Tassie than there is in Queensland. So, there's still something in that. It's getting less clear and we're understanding things less.

One of the other questions that was asked was what evidence is there if any of the impact of a cluster of autoimmune conditions in a genetic line contributing to MS. And that was one that I got asked very frequently. So, I was really glad someone put that question forward because it was in clinic someone said if I've got a long history of people in the family with autoimmune disease, does that give me a genetic risk? Vicki replied, this is another complicated question to answer. There are some autoimmune conditions which have a genetic basis that actually protects against MS and makes MS less likely. I suppose it would depend on which autoimmune conditions were present. And that was very similar to the way that we responded in clinic, to say that most of the research to date has been quite mixed in this area. There's been some research that's indicated people with certain chronic autoimmune conditions have a familial sort of family of different autoimmune things. And then in other research that wasn't clear, wasn't any strong indicators enough, I guess, to say, we need to go very strongly down this path because A often is so often correlated with B. And in my 20 years of MS nursing as well too, I didn't see any in 1, 500 people I looked after, which is, you know, a pretty big group there wasn't any particular. You know, lots of people had family members who had another autoimmune condition or one particular one. And so, I think the research out there on, on that linking of autoimmune conditions still needs a little bit more work to be done on that.

But at the same token, it was some families who you'd said, these all had some sort of autoimmune condition. So, whether that was just an unfortunate thing within that family or whether there's a genetic link to that, what Vicki was saying as well, too, in response to that question was, there's not a great deal of clarity on answers to that.

One other question was, is anyone following families with clusters of MS through time to see younger generations develop MS? And yes, there is a there's a researcher in Tasmania, Nicholas Blackburn, who's doing that work and often is interested in hearing about families who have MS. He's said that she's in the process of working with him to apply for more funding to work on this in the future. I'm sure he'd be happy to have his email sent to anyone who is interested in that piece of work. So, if you are interested in that a little bit more, please make sure to touch base.