How your genes affect your heart attack risk

Understanding how your genes can affect your risk of heart disease is vital to understanding what causes heart disease, and to unlocking new treatments.

Researchers have been working to piece together this puzzle for decades. In the 1980s American researchers discovered that an inherited mutation (fault) in a single gene could cause dangerously high levels of cholesterol, leading to an increased risk of coronary heart disease. But it soon became clear that there must be other genes that contribute to the risk of coronary heart disease.

The human genome carries over 3 billion ‘letters’ that make up our DNA. As the methods to sequence DNA became quicker and cheaper, the science of genomics was born. This is the study of the complete sequence of all the genes in any individual.

Being able to study the whole genome in large groups of people is a powerful tool for understanding the possible causes of disease. Genomic studies have shown that it is not only faults in single genes that can lead to disease. Many common variations in single letters of the DNA along our chromosomes (known as DNA polymorphisms) can together be important in altering our risk of disease. The BHF Family Heart Study was set up in the early 2000s by BHF Professor Stephen Ball from the University of Leeds and BHF Professor Sir Nilesh Samani from the University of Leicester, to explore this in heart disease.

The BHF Family Heart Study

The BHF Family Heart Study involved collecting blood samples for DNA testing from members of almost 2,000 families with a history of early heart attacks. Early analysis of the results suggested that small DNA changes (polymorphisms) in several areas of the genome affected the risk of having coronary heart disease. But the research team realised that a much larger study would be needed to pin down exactly where these changes were located, and what genes they affected. So the study was extended to include more than 190,000 people through an international research collaboration led by Professor Samani with BHF Professor Hugh Watkins at the University of Oxford and colleagues in Europe and the USA. In 2013 this study identified several new DNA changes that increase the risk of developing coronary heart disease. Most of them have very little effect on their own, but families that carry lots of these DNA variations are more likely to have heart attacks.

By using blood samples from UK Biobank, in 2018 Professor Samani and colleagues were able to calculate an individual’s “polygenic risk score” based on possible variations at over a million points along their DNA, and to show that by itself, the score could predict the risk of coronary heart disease as accurately as conventional factors such as cholesterol and blood pressure. More importantly, in people whose conventional risk score showed a moderately increased risk of early heart disease, their polygenic risk score could more accurately predict whether they would develop coronary heart disease in the next 10 years.

In future, doctors could use this score to prevent more heart attacks by better identifying people who are at risk, and therefore who could most benefit from lifestyle changes and preventive medication.

New genes – new medicines?

Finding the DNA changes that increase the risk of coronary heart disease is just the start. Many of these changes are in genes which are known to be involved in well known risk factors, such as cholesterol or blood pressure. But our researchers have also found changes in genes that have never before been linked to heart disease before; and some occur in DNA regions that we know very little about. This opens up a wealth of new possibilities for preventing or treating heart disease.

In 2007, the team behind the Family Heart Study found DNA changes on a part of chromosome 9, known as chr9p21, that nearly doubled the risk of coronary heart disease in some people. But the biology behind this remains a mystery.

In 2008 Professor Watkins’ team found that a gene called ANRIL, located on chromosome 9 and which hadn’t previously been known to be involved in heart disease, was a prime candidate to explain how chr9p21 is linked to heart disease, but it is still unclear how it works.

So we are currently funding BHF Professor Ziad Mallat at the University of Cambridge to explore further the role of ANRIL. His findings so far suggest that ANRIL controls the activity of specific genes involved in inflammation. This could mean that anti-inflammatory drugs may be able to slow the progress of coronary heart disease.

First published 1st June 2021