Genetic architecture of heart disease
For more than three decades Professor Sir Nilesh Samani has been at the forefront of research investigating the inherited basis of common cardiovascular diseases. These diseases include high blood pressure (hypertension) and coronary artery disease, the cause of angina and heart attacks.
Professor Samani’s ambition has been to truly comprehend why these diseases occur more commonly in some families but not others. This not an easy task as they have a substantial but complex genetic architecture requiring sophisticated deciphering.
By assembling some of the best clinical cohorts for his research, such as the British Heart Foundation Family Heart Study (BHF-FHS) and the Genetic Regulation of Arterial Pressure in the Community study (GRAPHIC), and working with national and international collaborators, Professor Samani has led efforts using the latest technologies to discover genetic changes in an individual’s DNA that increase their risk of heart disease.
Several hundreds of these changes have now been successfully identified, which has revolutionised our understanding of the causes of heart disease.
Risk-affecting genes
Professor Samani’s discoveries have major potential implications for science, development of new treatments, clinical practice, and patients. The new genes identified that affect the risk of developing coronary artery disease or hypertension offer opportunities to develop new treatments to tackle these major diseases. Professor Samani’s team have dissected the underlying mechanisms by which some of these genes affect risk, thereby helping this translation.
The discoveries have also had a profound impact on how the pharmaceutical industry prioritises their targets for drug development. Previously, they relied on observational and other more circumstantial evidence, which can sometimes be misleading. Now, they put much more emphasis on having genetic evidence of the type provided by Professor Samani’s research before embarking on a costly drug development programme.
Predicting and preventing
A potential benefit of equal, if not greater importance, arising from Professor Samani’s ground-breaking research, is the ability to identify people who are at increased risk before they develop the disease so that prevention measures can be initiated, halting the disease occurring at all.
Individually, each of the changes in DNA that his research has uncovered only has a small effect on risk but when combined into a genetic risk score (often called a polygenic risk score, PRS), this can partition individuals into very different lifetime trajectories of risk.
As Professor Samani explains: “A polygenic risk score is like the cards you are dealt with from a large deck, determined by which DNA changes your parents carry. Some people will, by chance, carry a lot of risk cards and others very few. We have shown, for example, that this can change an individual’s risk of developing coronary artery disease by a factor of three- or four-fold or more and that information on PRS adds to current clinical assessment of risk."
The additional, potentially major advantage is that DNA does not change with age. PRS can be assessed at any age, allowing those people at high genetic risk to be identified much earlier so that prevention measures can be targeted specifically to those at high risk – something that is often referred to as precision medicine. Most importantly, genetic testing is now available at a cost and scale to be now more widely accessible.
Professor Samani’s research has contributed to the enormous interest in the NHS and other health systems as to how to use PRSs effectively for patient benefit.
Biological ageing
While Professor Samani’s main interest has been in discovering and understanding the genetic changes that affect risk of cardiovascular diseases, almost as a side hobby, he has explored the role of biological ageing in cardiovascular diseases and in doing so opened up a completely new area of research.
He explains: “Many cardiovascular and other diseases are age-related but not an inevitable consequence of ageing. Also, why people with apparently similar risk factors develop their disease has always puzzled me in my daily clinical practice. Some of this variation is of course due to the genes each person inherits and the lifestyle and environmental factors they are exposed to, but I wondered whether there was something else. Because of the age connection of these diseases, I wondered whether the missing piece was related to biological ageing.”
This question sparked a journey over the last 20 years where he and his team have explored the relationship between telomere length and age-related diseases. Telomeres are the ends of chromosomes where they protect the chromosomes from damage. They vary in their average length between people and telomeres shorten to different extents as people age. Telomere length is therefore considered a marker of biological age.
Professor Samani was the first to show that shorter telomere length, indicating greater biological age, is associated with higher risk of coronary artery disease, independently of chronological age and other risk factors. His team also showed that telomere strength is highly heritable and identified the first genetic changes that influence telomere length. Using these DNA changes, they showed that the association between shorter telomeres and risk of coronary artery disease is causal.
Their work and discoveries have sparked a worldwide interest in the role of telomeres and biological ageing in age-related diseases and whether this could be an amenable therapeutic target. Very recently his team have completed the heroic task of measuring telomere length in almost half a million participants in UK Biobank creating the world’s largest resource to explore the determinants and biomedical consequence of inter-individual variation in telomere length.
