How your DNA determines whether aspirin protects you from heart attacks
When you pop an aspirin for heart health, you might assume it's working exactly as intended. But for millions of people, this common medication fails to provide adequate protection against heart attacks and strokes. This phenomenon of "aspirin resistance" has puzzled doctors for decades. Why would a standard dose of aspirin work well for some people but poorly for others?
Approximately 20-30% of people may have reduced response to standard aspirin therapy, putting them at higher risk for cardiovascular events 1 2 .
The answer may lie in our genes. Groundbreaking research has revealed that our genetic makeup significantly influences how our platelets—those tiny blood cells responsible for clotting—respond to aspirin. In a landmark study called GeneSTAR (Genetic Study of Aspirin Responsiveness), scientists embarked on a mission to uncover the genetic factors that determine why aspirin's protective effect varies so dramatically from person to person 1 2 . What made this study particularly innovative was its approach: combining two powerful genetic methods to hunt for these aspirin-response genes across different ethnic groups.
Platelets are small, disc-shaped blood cells that play a critical role in stopping bleeding by forming clots. When you get a cut, platelets rush to the site and stick together, forming a plug. However, this same process can become dangerous when it happens inside blood vessels, leading to heart attacks and strokes when clots block critical arteries 2 .
Aspirin, one of the most widely used medications worldwide, works by inhibiting platelet function. Specifically, it blocks an enzyme called cyclooxygenase-1 (COX-1), which platelets need to become activated and form clots 2 . By making platelets less "sticky," aspirin reduces the risk of dangerous clot formation.
Just as we inherit genes that determine our eye color or height, we also inherit genetic variants that influence how our platelets function. Heritability studies suggest that 40-60% of the variation in how people's platelets respond to aspirin is genetically determined 8 . This means our DNA contains important clues about why aspirin works well for some people but not for others.
Until recently, most genetic studies of cardiovascular disease focused on European populations. The GeneSTAR study broke new ground by including both European American and African American participants, acknowledging that genetic factors might differ across ethnic groups 1 2 . This was crucial for ensuring that future genetic insights would benefit diverse populations.
This approach looks for genetic markers that are inherited along with a particular trait (like aspirin response) within families. It's particularly good for identifying regions that might harbor rare genetic variants with large effects 1 .
This method scans thousands of genetic markers across the genome in unrelated individuals to find variants that occur more frequently in people with a particular trait. GWAS excels at detecting common variants, though each might have only a small effect 4 .
The GeneSTAR study's innovative approach was to combine both linkage and association methods. By using these complementary techniques, researchers could prioritize genetic regions that showed evidence from both approaches, increasing their confidence in the findings 1 2 . As one researcher noted, "The combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up" 1 .
The GeneSTAR researchers recruited 1,231 European American and 846 African American healthy participants from families with a history of premature coronary artery disease 1 2 . All participants were given a low dose of aspirin (81 mg) daily for two weeks—the standard preventive dose recommended for heart health.
Before and after the aspirin trial, researchers conducted extensive testing of platelet function using 37 different measurements 1 . These tests measured how strongly platelets responded to various stimuli that normally trigger clotting, such as collagen (which platelets encounter when a blood vessel is damaged), ADP (a natural chemical that activates platelets), and epinephrine 2 .
2,077 participants from families with history of coronary artery disease
37 platelet function measurements before aspirin treatment
81 mg/day for 14 days
Same 37 measurements repeated after aspirin course
Combined linkage and association approaches
The genetic analysis followed a meticulous multi-step process:
The team used microsatellite markers (repeating sequences of DNA that vary among individuals) to scan the genome for regions linked to aspirin response 1 .
Finally, they integrated findings from both approaches, giving more weight to association signals that also showed evidence of linkage 1 .
| Participant Characteristics in the GeneSTAR Study | ||
|---|---|---|
| Characteristic | European American | African American |
| Number of Participants | 1,231 | 846 |
| Family History | All from families with premature coronary artery disease | All from families with premature coronary artery disease |
| Aspirin Dosage | 81 mg/day for 14 days | 81 mg/day for 14 days |
| Platelet Function Tests | 37 different phenotypes measured before and after aspirin | 37 different phenotypes measured before and after aspirin |
The GeneSTAR study identified several genomic regions connected to how people's platelets respond to aspirin. One of the most significant findings was a region on chromosome 5q11.2 in African Americans that showed strong linkage to post-aspirin platelet response to ADP 1 . This region contained several genetic markers with "suggestive" and "significant" evidence of linkage, meaning the statistical support for this finding was strong.
Additionally, the researchers discovered that ten additional factors had suggestive evidence for linkage to thirteen different genomic regions 1 . Notably, all but one of these factors were related to aspirin response variables rather than baseline platelet function, highlighting that the response to medication has a distinct genetic architecture separate from native platelet behavior.
| Significant Genomic Regions Identified in the GeneSTAR Study | |||
|---|---|---|---|
| Chromosomal Region | Population | Phenotype | Significance Level |
| 5q11.2 | African American | Post-aspirin response to ADP | Significant (p < 2×10⁻⁵) |
| 13 additional regions | Both | 10 aspirin response factors | Suggestive (p < 7×10⁻⁴) |
When the researchers looked at the genome-wide association results alone, only 9 SNPs across 11 factors met the strict threshold for genome-wide significance 1 . However, when they weighted the association signals by also considering the linkage evidence, they identified 30 SNPs with significant associations 1 .
This demonstrated the power of their combined approach—by requiring evidence from both methods, they could identify genetic signals that might have been missed using either method alone.
SNPs identified by GWAS alone
SNPs identified by combined approach
Increase in discovery power
| Essential Research Tools in Platelet Genetics | |
|---|---|
| Research Tool | Function in Study |
| Illumina 1M Genotyping Array | Enabled genome-wide association analysis using ~1 million single nucleotide polymorphisms (SNPs) 4 |
| Microsatellite Marker Set | Allowed genome-wide linkage analysis with 550 short tandem repeat markers 1 |
| Platelet Aggregometer | Measured platelet aggregation in response to various agonists (ADP, collagen, epinephrine) 2 |
| Enzyme-linked Immunosorbent Assay (ELISA) | Quantified urinary 11-dehydro-thromboxane B₂ levels, a marker of platelet activation 2 |
| Principal Component Analysis | Statistical method to reduce 37 platelet phenotypes to independent factors for analysis 1 |
While the initial study identified genomic regions linked to aspirin response, understanding the specific genes involved and their biological mechanisms requires further investigation. Subsequent research has confirmed the importance of several genes in platelet function, including PEAR1 (platelet endothelial aggregation receptor 1) and RGS18 (regulator of G-protein signaling 18) 8 .
The PEAR1 gene, in particular, appears to play a crucial role in how platelets respond to aspirin. One study found that a specific genetic variant in PEAR1 was associated with platelet function both before and after aspirin treatment 4 . The minor allele of this variant was linked to both decreased platelet aggregation and increased risk of gastrointestinal bleeding—demonstrating how genetic insights can reveal both benefits and risks of antiplatelet treatments 8 .
Platelet Endothelial Aggregation Receptor 1
Regulator of G-protein Signaling 18
The findings from the GeneSTAR study and subsequent research bring us closer to the goal of personalized medicine for cardiovascular disease. Instead of a one-size-fits-all approach to aspirin therapy, doctors may eventually be able to use genetic testing to identify:
Individuals who are likely to get strong protection from standard aspirin doses
Those who might need alternative or additional antiplatelet medications
Patients who might be at higher risk for bleeding side effects
"In order to have useful clinical applications, variants must have large effects on a modifiable outcome" 5 .
While we're not yet at the point where routine genetic testing for aspirin response is standard practice, studies like GeneSTAR are building the foundation for that future.
The GeneSTAR study's innovative combination of linkage and association approaches has advanced our understanding of why people respond differently to aspirin. By revealing the genetic architecture underlying platelet function and aspirin response, this research challenges the notion that every patient should receive the same antiplatelet therapy.
As we continue to unravel the complex relationship between our genes and how we respond to medications, we move closer to a future where treatments can be tailored to our individual genetic makeup. The path from genetic discovery to clinical application is long, but each study like GeneSTAR brings us one step closer to truly personalized cardiovascular care.
As one review on platelet genetics aptly stated, "Studies of common genetic influences, even of small effect, offer additional insights into platelet biology including the importance of intracellular signalling and novel receptors" 5 . Beyond potential clinical applications, these genetic findings provide fundamental insights into platelet biology that might reveal new targets for drug development.
The next time you take an aspirin, remember that its effectiveness depends not just on the pill itself, but on the unique genetic blueprint that determines how your body responds to it.