Unraveling Atherosclerosis
For decades, atherosclerosis was considered a simple plumbing problem. Genetics is revealing a far more complex and fascinating story.
Atherosclerosis, the slow and silent buildup of fatty plaques in our arteries, is the underlying cause of about 50% of all deaths in Western societies1 . It can lead to heart attacks, strokes, and peripheral artery disease, often without any warning. For years, the conversation focused on lifestyle factors like diet and smoking. While these are critically important, they don't tell the whole story. Why does one lifelong smoker live to 90 with healthy arteries, while another suffers a heart attack at 45? The answer lies deep within our genetic code. This article explores how scientists are deciphering the hereditary blueprint of atherosclerosis, revolutionizing our understanding of one of humanity's most pervasive health threats.
Atherosclerosis is not a classic hereditary illness caused by a single gene mutation. Instead, it is a complex and heritable disease involving multiple genetic variants, each contributing a small amount to the overall risk2 . Think of it not as a destined fate, but as a loaded genetic hand of cards. How that hand is played—through lifestyle and environment—determines the ultimate outcome.
Heritability studies estimate that our genes account for 30–60% of our susceptibility to atherosclerotic cardiovascular disease8 . This genetic influence doesn't usually operate directly but works through intermediate traits. Key risk factors like high blood pressure and elevated cholesterol levels are themselves strongly influenced by genetics1 8 .
The disease process begins when low-density lipoprotein (LDL) cholesterol particles accumulate in the artery wall, triggering a chronic inflammatory response1 . This inflammation is driven by immune cells and can be influenced by genetic differences in how our bodies manage both lipids and inflammation.
Finding the genes involved in a complex disease like atherosclerosis is a monumental task. Researchers use two primary, powerful strategies to hunt for these genetic needles in a haystack.
This traditional method starts with a hypothesis. Scientists identify a gene known to be involved in a relevant biological pathway—such as lipid metabolism or inflammation—and then investigate whether different versions of that gene (polymorphisms) are found more often in people with atherosclerosis7 .
This approach successfully identified the crucial role of the Apolipoprotein E (APOE) gene, located on chromosome 195 . Different forms of the APOE protein affect how efficiently cholesterol is cleared from the blood, directly influencing a person's blood cholesterol levels and, consequently, their risk of atherosclerosis5 .
In contrast, genome-wide studies are hypothesis-free. Researchers scan thousands of genomes, looking at millions of genetic markers to see which ones are consistently associated with the disease in large populations. The most impactful of these are Genome-Wide Association Studies (GWAS).
A landmark 2025 GWAS, the largest of its kind, used advanced CT angiography to scan the coronary arteries of over 24,000 individuals4 . Instead of just waiting for a heart attack to happen, this study directly measured the genetic links to the actual plaque burden in the arteries. It identified 20 significant independent genetic markers linked to the amount of plaque, three of which were in entirely new locations not previously connected to heart disease4 . This demonstrates the power of modern genetics to uncover completely novel aspects of the disease.
| Genetic Locus | Function / Note |
|---|---|
| LPA-PLG | Involved in lipoprotein(a) production; a major risk factor. |
| COL4A1-COL4A2 | Related to the structure of the arterial wall. |
| CDKN2B-AS1 | A region also implicated in several other vascular diseases. |
| APOE | Confirms the role of lipid clearance pathways. |
| TRIB1 | Influences both lipid metabolism and inflammation. |
| EDNRA | Primarily associated with carotid plaques; less with coronary. |
While human GWAS pinpoint associations, proving that a gene actually causes disease requires experimental models. For decades, the humble mouse has been an indispensable partner in this quest.
Wild-type mice are naturally resistant to atherosclerosis, so researchers have developed specialized genetic models. The process typically follows these steps2 :
Researchers use two primary mouse models lacking key genes for clearing lipids from the blood: the Apolipoprotein E knockout (Apoe−/−) mouse and the LDL receptor knockout (Ldlr−/−) mouse. These mice develop high cholesterol and atherosclerosis.
Scientists cross these susceptible mice with another mouse strain that has a specific gene of interest "knocked out" or deactivated.
The resulting double-mutant mice are fed a special high-fat "Western-style diet" to accelerate plaque formation2 .
After a set period, researchers measure the size and character of atherosclerotic plaques in the mouse aortas and compare them to control mice. They also track blood cholesterol levels to see if the gene's effect is independent of lipids.
Using this powerful method, scientists have tested the role of over 100 different genes in atherosclerosis2 . The results are telling:
Gene deletions that reduced plaque size
Gene deletions that increased plaque buildup2
Crucially, this work revealed that atherosclerosis is not just a lipid disorder. About two-thirds of the genes that affected plaque size did so without substantially altering blood cholesterol levels2 . This proved that genes involved in inflammation, immune cell function, and arterial wall integrity are central players in the disease.
| Gene | Function | Effect on Atherosclerosis in KO Model | Effect on Plasma Cholesterol |
|---|---|---|---|
| Cav1 | Caveolin-1, involved in cellular transport | Decrease | Increase |
| IL6 | Pro-inflammatory cytokine | Increase | Increase |
| Lep | Leptin, regulates appetite | Increase | Increase |
| Cd36 | Scavenger receptor on macrophages | Decrease | Decrease (in VLDL-TG) |
| Il1r1 | Receptor for interleukin-1 (inflammation) | Decrease | No significant change |
Behind every discovery is a set of sophisticated tools. The following reagents and models are the workhorses of genetic atherosclerosis research.
| Research Tool | Function / Explanation |
|---|---|
| Apoe−/− and Ldlr−/− Mice | Genetically modified mouse models that develop high cholesterol and atherosclerosis, serving as the standard experimental background2 . |
| Western-Type Diet (WTD) | A high-fat, high-cholesterol diet used to accelerate plaque formation in animal models, mimicking a pro-atherogenic human diet2 . |
| Gene Co-expression Network Analysis | A bioinformatics method that identifies groups of genes (modules) with similar expression patterns, revealing coordinated biological pathways. |
| Coronary CT Angiography (CCTA) | A non-invasive imaging technology that allows researchers to directly visualize and quantify coronary plaque burden in human studies4 . |
| GWAS Genotyping Arrays | Microchips that can rapidly genotype hundreds of thousands to millions of genetic variants across the human genome in a single experiment4 8 . |
The ultimate goal of this genetic detective work is to save lives. The discoveries are already paving the way for a new era of medicine.
Every new gene discovered opens a potential door for therapy. For example, the identification of the PCSK9 gene through the study of familial hypercholesterolemia led to the development of highly effective PCSK9 inhibitor drugs, which dramatically lower LDL cholesterol and reduce cardiovascular events9 .
In the future, a polygenic risk score—which combines the small effects of hundreds of genetic variants—could help identify individuals at high risk long before any symptoms appear, allowing for early, personalized prevention strategies4 .
Perhaps most importantly, these genetic findings are forcing a re-evaluation of the disease. The 2025 GWAS highlighted genes like COL4A1-COL4A2, which are involved in the structure of the artery wall itself4 . This suggests that the very integrity of our arteries is a genetic factor in atherosclerosis.
The journey to fully decode the genetics of atherosclerosis is far from over. It is a story still being written, one base pair at a time. But with each new gene discovered, we move closer to a future where this silent killer can be seen, understood, and stopped.