Prof Aroon Hingorani - Heart risk genes

Kat - A heartbeat is the sound of life itself, and our hearts beat thousands of times a day, pumping blood around the body. But things can go wrong. Cardiovascular diseases - such as heart attacks and strokes -  are responsible for around one in four deaths here in the UK, and someone in the country dies of a heart attack every seven minutes. As you might expect, genes play a role in our individual risk of heart problems, so I spoke to Professor Aroon Hingorani, director of the UCL Institute of Cardiovascular Science to find out what we know so far about the genetics of heart disease.

Aroon - There's been an increase in our understanding of a lot of genes in cardiovascular disease over the last decade or so. So, it's long been known that heart disease tends to run in families. There are few rare conditions that are caused by single genes. They tend to be quite rare, but the genetic effects tend to be quite large. Most of the common cardiovascular diseases in late life also have a genetic contribution. The model has been that probably, the risk is increased by small effects of a very large number of genes and the challenge has been to try and identify those genes.

Kat - So, if you have a lot of these kind of bad variations, you're much more likely to get heart disease or a related condition. And if you only have a few, your risk is lower.

Aroon - Exactly right. So, the challenge has been to try and identify which are the points in the genome where these variants lie that influence disease susceptibility. So, over the last 10 years or so, there's been an increase in our understanding of this, through what are called genome-wide association studies. Typically, what these do is that they compare the frequency of these common variants in the genome between people who have the disease and people who don't. And where there's a difference in frequency variance in the disease cases versus the control, that highlights a point in the genome that contain genes that includes disease risk. So, for coronary heart disease for example, we know that there are about 46 or so regions of the genome that imprints all risk of suffering a heart attack.

Kat - We hear all the time that there are things about diet and exercise, and salt, and all these things we can do to reduce that risk of cardiovascular disease. What proportion is the influence that's in our genomes?

Aroon - It's clearly immensely important that dietary and lifestyle factors are corrected to reduce the risk of cardiovascular disease. So, the things that are particularly important are diets high in saturated fat and high salt, which influence cholesterol and blood pressure which are known to be causal factors in heart disease. The genetics and the environmental factors act in an interplay, so I don't think we can divorce from the other. Clearly, you can modify your environment; you can't modify your genome. What the genetic studies do is they highlight those pathways and those environmental exposures that are causally related to disease. So, they can actually give insight into the sorts of things that we should be modifying or treating with drugs to reduce disease risk.

Kat - Where have we got to in terms of translating the things that we've discovered from these big studies into the clinic? How close are we to that?

Aroon - So, there's probably two main areas where people are trying to utilise genetic information to improve personal and public health. One is to try and use the information to try and better predict who's going to get a cardiovascular event in later life. The other is to use the information to understand the mechanisms of heart disease a little bit better. One problem with the first translational opportunity, the use of genetic variants to try and improve prediction of future disease risk, is that the effects of each variant tends to be quite small. Now of course, there are people in the population who carry a larger number of risk variants who are at higher risk of disease. But they tend to be relatively small in number. Most of us carry an intermediate number of risk variants that influence our risk of disease.

A particularly exciting area though is the use of the genetic information to understand the mechanisms by which disease risk is increased because through understanding the mechanism, it should become possible to develop new therapies to treat or prevent heart disease risk.

Kat - So, how can you do that? How can you mine all these genetic data to find new targets?

Aroon - That's a really interesting question and it's an area that we're actively pursuing. Let me illustrate this with an example. There are drugs called statins that are widely used in the treatment and prevention of cardiac disease. They work by lowering LDL cholesterol, a risk factor for heart disease. So, it turns out that when the genome-wide association studies were done, one of the genes that came up being associated with an increase risk of disease was the gene that encodes the protein which is the target of statin drugs. It's called HMG-CoA reductase. So, one can do a sort of thought experiment and ask the question that if the drug haven't been invented, but the genetic information was known, that would've motivated the development of the drug at that time.

Kat - So, you were looking for people who naturally have lower levels of this and if they have a low risk of heart disease, you can go, "Oh well, maybe lowering that protein would work."

Aroon - Correct. So, targeting that protein might be a good way of preventing heart disease in people who don't carry that variant. So, we've been working ,and others have as well, in trying to mine the genetic information from genome-wide association studies and try and utilise it, to try and identify those pathways in proteins that might be most amenable to targeting with new treatments to reduce heart disease risk.

Kat - What do you think are the most promising targets so far? What have you found in this data trove?

Aroon - So, that's very much work in progress, but what I can say is that there are some exciting opportunities that we think will arise from this sort of activity. I guess the challenge over the next five to 10 years is to capture that information, prioritise it because it's a lot of data there - it's a big data problem - and to try and identify those proteins in pathways where the translational opportunity is foremost, once that we could try and capture early on.

Kat - Where have we come in recent decades in making an impact in improving outcomes in heart disease and where would you like to see us go over the next say, 10 to 20 years?

Aroon - So, it's interesting that the epidemiology of cardiovascular disease is changing globally. So, in high income countries, there's actually been a fall in cardiovascular mortality through better public health measures, better acute treatments, and better preventative treatments, and through reduction in smoking. So, public health measures have had a key role to play. But more people are living with the consequences of cardiovascular disease including heart failure and arrhythmias. Actually, we do need new therapies for those disorders because there's a substantial unmet need in those areas.

There's also a concern that in low and middle income countries, rates of cardiovascular disease are increasing and eventually, may outstrip infectious diseases. A particular concern is the epidemic of obesity and type 2 diabetes. Both of which are risk factors for cardiovascular disease. So, in high and middle income countries, we can say there's been some success, but there are new challenges, people living with the consequences of heart disease. And in low and middle income countries, there are increasing rates of heart disease which pose a challenge.

Kat - That was Professor Aroon Hingorani from UCL.