It’s All in the Genes

Issue 53
Feb 2025

AFFAIRS OF THE HEART

By Professor Shu Ye, Cardiovascular-Metabolic Disease Translational Research Programme, NUS Yong Loo Lin School of Medicine

Recent studies of the genetic makeup of patients with cardiovascular diseases indicate many genetic variants associated with these diseases.

Blood vessels are hollow tubes that transport blood to provide oxygen and nutrients throughout the human body. If some of these tubes become narrowed or blocked, blood supply to certain parts of the body will decrease, which may lead to severe illnesses such as ischaemic heart disease, stroke, and chronic kidney disease. These cardiovascular diseases affect many people worldwide, with ischaemic heart disease alone being responsible for over 20% of all deaths in Singapore—according to data from the Singapore Heart Foundation.

It is well known that lifestyle factors such as unhealthy diet, a lack of physical exercise and cigarette smoking, increase the likelihood of cardiovascular diseases. However, some people are more susceptible to such diseases than others, due to differences in their genetic makeup. Recent studies comparing the genetic makeups of cardiovascular disease patients and those of healthy individuals have found many genetic variants (DNA sequence variants) that likely predispose some persons to cardiovascular diseases.^1,2

The discovery of these genetic variants is a very important finding, as it can be utilised to guide further research to gain a better understanding of how cardiovascular diseases occur, facilitate the development of new treatments, and aid the invention of new methods for identifying persons who are at high risk of developing such diseases.

Ischaemic heart disease is responsible for over
20%
of all deaths in Singapore

New insights into how cardiovascular diseases develop

Research has shown that some genetic variants cause ischaemic heart disease by raising the levels of lipids in the blood. These genetic variants affect certain genes involved in the handling and removal of lipids in the body, leading to an increase in lipid levels. The excessive lipids are deposited in the blood vessel wall, resulting in a build-up of oily materials that narrow the blood vessel, thereby causing the disease.

In contrast, some genetic variants do not affect the lipid level but instead act on cells in the blood vessel wall.^3,4 The blood vessel wall comprises endothelial cells, smooth muscle cells and some other types of cell. Recent research has revealed that some genetic variants affect the function of endothelial cells or the behaviour of smooth muscle cells. For example, some genetic variants promote smooth muscle cell growth, leading to a build-up of abnormal tissue (called atherosclerotic plaque) in the blood vessels and, consequently, ischaemic heart disease.

Identification of novel drug targets

Following the discovery of genetic variants that predispose individuals to cardiovascular disease, recent research has revealed many genes affected by these genetic variants. Some of these genes represent potential targets for developing new drugs for prevention and treatment of cardiovascular disease.

For example, some ischaemic-heart-disease-causing genetic variants affect the SORT1 gene that encodes the protein called Sortilin.⁵ Sortilin plays an important role in lipid metabolism and represents a potential drug target. There is ongoing development of Sortilin targeted therapeutics.

Currently available treatments for ischaemic heart disease include lowering lipid levels, controlling blood pressure, and thinning the blood. However, some genetic variants cause cardiovascular disease through mechanisms independent of lipid levels or blood pressure. For example, these disease-causing variants affect vascular endothelial cells or smooth muscle cells, without influencing lipid levels or blood pressure. Therefore, the genes affected by these genetic variants represent potential targets for the development of novel drugs that can act on such vascular cells. Such a class of novel drugs could complement currently available treatments that target lipid levels and blood pressure. Recent research at the National University of Singapore has identified a panel of such novel potential drug targets.⁴

The greater the number of genetic variants a person carries, the higher their risk of developing cardiovascular disease.

Development of methods for identifying individuals who are at high risk of developing cardiovascular diseases

Some people carry many genetic variants associated with cardiovascular disease, putting them at higher risk of developing the disease. Others carry fewer genetic variants and face a lower risk. In other words, the greater the number of genetic variants a person carries, the higher their risk of developing cardiovascular disease.

Recent research has also led to the development of polygenic risk scores based on the total number of disease-causing genetic variants. Such polygenic risk scores are currently being studied for their utility as a means to identify at-risk individuals for early therapeutic intervention to prevent cardiovascular disease development and progression.⁶

In summary, cardiovascular diseases is the leading cause of mortality and morbidity in Singapore and many other countries. Recent studies of the genetic makeups of patients with such diseases have uncovered many genetic variants associated with these diseases. Ongoing research in this field aims to translate these important findings into the development of new drugs and methods for identifying at-risk individuals. These research efforts have shown encouraging promise in these areas.

Aragam KG, Jiang T, Goel A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022;54:1803-1815.
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50:524-537.
Schnitzler GR, Kang H, Fang S, et al. Convergence of coronary artery disease genes onto endothelial cell programs. Nature. 2024;626:799-807.
Solomon CU, McVey DG, Andreadi C, et al. Effects of Coronary Artery Disease-Associated Variants on Vascular Smooth Muscle Cells. Circulation. 2022;146:917-929.
Musunuru K, Strong A, Frank-Kamenetsky M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714-719.
Khera AV, Emdin CA, Drake I, et al. Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. N Engl J Med. 2016;375:2349-2358.