Prof Hugh Watkins - Sudden heart death

Kat - Premiership footballer Fabrice Muamba hit the headlines in 2012 when his heart stopped on the pitch for more than an hour. Incidents like this are usually due to inherited gene faults, which are often not known about until disaster strikes. British Heart Foundation Professor Hugh Watkins, at the Wellcome Trust Centre for Human Genetics in Oxford, is trying to track them down.

Hugh - So, I look at conditions that cause young people, mostly kids, teenagers, young adults, to be at risk of catastrophic changes in the function of the heart that just cause you to drop down dead. And so, the uncommon, they're not unheard of. You'll have seen them in the public eye. So, when this happens in the public form often in sports, it's a young sports player, it's usually one of these familial conditions that causes it.

Kat - And so, by understanding these genes, this is directly changing the way that you work with families to do this.

Hugh - Yeah, absolutely. So, in my clinic, I will use DNA testing on a routine daily basis and it completely transforms the way we do work. So, that's very exciting. Some of these conditions are not very easy to diagnose by clinical tests. And so, when you think someone's got one or you find they've definitely got one or sometimes it happens quite commonly as a tragedy, you only work out after they died what they had. The question then comes, "Who else is at risk in the family?" And because it's one gene that comes down to maybe your mum or your dad, by and large, each immediate family relative has a 50/50 chance of that condition.

And so, what we now know is that for most of these conditions and there are many different ones with long names, there's usually a bunch of genes that could do it. In each gene, there would just be one gene change. So, if we have a person who's definitely got the condition, we will do a fairly large genetic analysis for all the genes, looking for that single 'spelling mistake'. If we can find it and be confident we have found it - it isn't always easy - that's a really powerful tool for then saying, "Who in the family might be at risk or who is not?" And the beauty of it is, that if you don't have that gene change then you won't have the condition and you don't need to be followed up and nor your kids. So, it's a very powerful way when there's been one of these alerting cases, and sometimes a tragedy case, to then work out who else we need to worry about. And we've got quite good cardiology treatments for people if we can diagnose them with these conditions.

Kat - Because it's all very well to find genes and say, "You're at risk" but if there's nothing you can do to intervene, that's not helpful. So, this is great - there's something you can do.

Hugh - It is. I mean, if you had nothing to offer, you probably wouldn't want to do this work at all. You would want to tell somebody that they're at risk if you couldn't improve it. If we find an individual who's clearly a high risk, we can implant a device like a glorified pacemaker that sits there and monitors the heart. If the patient has one of these sudden chaotic life-threatening heart rhythms, the machine will charge up and give electric shock just like you can see in the patterns in television dramas like Casualty, and that's life-saving. But these are complex, scary, sometimes dangerous devices that you don't want to use if you don't need to.

So, in another part of the programme of work is ask the question, now we know what the genes are and we can define what proteins that the genes code for, you'd think that would give us a clue as to what the disease pathways are. And that's a big thrust of our work and it's gone quite a long way. We now have some quite tangible and testable ideas, and are beginning to do clinical trials with new treatments. They're looking very promising.

Kat - So, that's one aspect of your work, but another aspect is looking more broadly at heart disease-associated conditions to find the complex susceptibility genes. Where has that got to now?

Hugh - A better story now than it was a few years ago, We started this work as did many groups in universities around the world, probably 10, 12, maybe even 15 years ago, and it's proved to be much harder than we thought. The reason is, as you will know, is that there's not one gene for heart attack or one gene for diabetes. There aren't 5, 10 or 20. There are hundreds, potentially, thousands of genes or changes in genes that make people just very slightly more or less at risk. And so, it's only recently that we had powerful enough genetic tools and big enough clinical studies that we can begin to find genes. Actually, we are now doing analyses on tens of thousands of patients.

When you do that then you do find these genes. Our list at the moment in terms of what we've published is around 46 newly identified genes which makes you a bit more likely to get a heart attack. It's exciting because they're not by and large the obvious genes we would've guessed. Some of them are. Some of them are genes that regulate how you handle cholesterol in the body and it's reassuring that we could get those positive controls. Some of them, we thought we knew what the gene did or the protein that it codes for did, but wouldn't have guessed it was involved in coronary disease or heart attack.

So, that's quite surprising. The fair number, we have no idea what they do. And so, that's good and bad. The good news is, there's a lot of opportunity for new biology. If we can understand new pathways that cause you to have a heart attack, there's lots of scope there for new drugs and medicines to stop it.

Kat - And there is this sort of idea that you'll be able to have a genome scan and will know your risk and you do this and take this drug, and do that, and you'll never get a heart disease.

Hugh - Yes, it's quite a nice dream, but it's a bit of a pipe dream. If you unpack all the sort of two or three components of the aspiration, one was that you could do the genome scan and predicting individual's risk. That's not looking very effective at the moment. So, most of us are fairly average in our genetic risks. If you take someone in a clinic and look at their hundreds of genes that contribute to their risk, they're not very likely to be very high or very low. If you do the whole population and find people that were high and low and that might work. But for an individual, it doesn't work so well.

And then the other thing is we've already got pretty good tools. They're not perfect but very powerful affects - age, gender, smoking, cholesterol, blood pressure, diabetes - are really quite strong predictors of heart risk. It's quite a high ask for genetics to make that better. So, at the moment, I don't think we look at this complex genetics as a tool for prediction. But rather, it's a tool for maybe classifying people into broad groups, but particularly, for trying to come up with new targets and new treatments. So, I'm very optimistic it will work, but actually, it will take time. 

Kat - That was Professor Hugh Watkins, from the Wellcome Trust Centre for Human Genetics.