Key takeaways:
- The ITGB3 gene encodes a protein receptor on the surface of platelets.
- A variant in the gene, called PlA1 or PlA2, is associated with increased clotting.
- The ITGB3 PlA2 variant is also associated with susceptibility to certain viruses. The variant protects against Hantavirus infection and alters the risk of Covid.
The ITGB3 Gene and the PlA1/A2 Variant
The ITGB3 gene codes for the beta-3 subunit of an integrin receptor. This is a receptor found on the surface of platelets that plays an important role in how platelets stick together to form a blood clot. The integration protein (integrin alpha IIb/beta3) binds to fibrinogen when activated to help platelets clump together into a clot.
The ITGB3 gene is also referred to as GPIIIa, glycoprotein IIIa, or CD61 in studies.
A common variant in the gene was identified decades ago, and the two alleles were named PlA1 and PlA2 (or PIA1/A2). In addition, the ITGB3 protein is involved in cell-to-cell adhesion as well as the migration of cancer cells.
(Note: This gene is not the same as the PAI1 gene – platelet activation inhibitor-1 gene, which is also involved in clotting. The similar allele names make it a bit confusing.)
Clotting cascade: Role of ITGB3
Clotting is vitally important when you cut yourself — but clotting too much or too quickly can also be a problem. Platelets are activated, and the integrin receptor binds to fibrinogen to stabilize the clot. While a necessary process, excessive clotting can cause heart attacks and strokes. Additionally, blood clots that form in the large veins of the leg or arm can cause deep vein thrombosis (DVT).
This is where the two ITGB3 variants, PlA1 and PlA2, come into play, with the PlA2 variant increasing clot risk due to increased platelet aggregation.
The prevalence of the PlA2 SNP varies quite a bit by ancestry. The PlA2 variant (CC or CT genotype below) is found in about 25% of people with Caucasian or African ancestry, but it is only found in 1-2% of people with Chinese or Japanese ancestry.
The ITGB3 PlA1/A2 variant and increased cardiovascular risk:
Hundreds of studies have been done on the ITGB3 genetic variant known as PlA1/A2. Here is an overview of some of the findings:
- Faster clotting: A study of men aged 20-25 found that those carrying the A2 variant had faster blood clotting times.[ref]
- Heart attacks at a younger age: A study of men who died of sudden cardiac death found that the A2 variant more than doubled the relative risk of sudden cardiac death under the age of 50.[ref]
- An overall meta-analysis combining the data from 14 studies concluded a statistical increase in the risk of heart attacks exists, with the increase in relative risk being higher in younger people (absolute risk still low).[ref]
- Sex differences for DVT: The results of one study that included both men and women found that only women who carried the A2 variant were at a higher risk of deep venous thrombosis.[ref]
- Atherosclerosis: Researchers looked at 1,202 Caucasian patients in an atherosclerosis study and found that the A2 variant carriers may be predisposed to an “increased risk of atherosclerotic plaque rupture.”[ref]
- A study of Pakistani patients found the variant has no impact on aspirin resistance.[ref]
Recurrent miscarriage risk factor:
Increased clotting can be a problem in pregnancy and increases the relative risk of miscarriage.
- Women carrying the variant may be at an increased risk of having recurrent miscarriages.[ref]
- Another study in women who had miscarried previously showed that the PlA2 allele was associated with increased platelet reactivity.[ref]
Platelets and the Immune Response:
Your circulating platelets also play an important role in detecting and binding to viruses. Different types of viruses can interact with surface receptors on platelets, and platelet activation plays a role in the body’s response to viruses.
Some viruses bind to receptors found on the surfaces of platelets (as well as other cells), and some viruses, such as adenoviruses, use cell surface receptors for viral entry. The integrin proteins, especially β3 integrins (ITGB3), are important in binding to viruses and for cell entry.[ref][ref][ref]
Asthma: The immune response is also important in allergic asthma. Interestingly, in the lungs, increased expression of ITGB3 reduces allergic asthma response and decreases inflammation.[ref]
Related article: Asthma and genetic susceptibility
Multiple sclerosis: A 2025 study showed that patients with relapsing-remitting MS had higher-than-normal expression of ITGB3, leading to greater platelet activation during times of MS flare-ups. The researchers theorize that high ITGB3 expression increases the neuroinflammatory pathways in peripheral blood immune cells, and this is likely controlled by microRNAs that affect both ITGB3 and other MS-related cytokines.[ref]
Related article: MS genes
ITGB3 variants and protection from the hantavirus:
Most genetic variants that have a downside also have a positive one: There usually is a reason the variant survives in the population. Tradeoffs.
The downside of the A2 variant is obvious – increased relative risk of early heart attack deaths, especially before the time of modern medical care. Since carrying this ITGB3 gene variant increased early heart attack deaths, at some point, the variant should have dwindled out in the human genome. Balancing out this negative is a positive reason the variant is still found in the population. In this case, the ITGB3 variant is thought to offer protection against a couple of viruses.
The hantavirus is a virus spread by mouse and rat feces that causes increased vascular permeability and decreased platelet clotting.[ref]Research shows that the hantavirus can use the beta-3 integrin receptor for cell entry, allowing the virus to enter platelets and other cells to replicate.[ref][ref] There are multiple strains of hantavirus, including an Andes virus strain and hantavirus strains found in the southwest and mountainous regions of the US. Carriers of the A2 variant are less likely to get sick from the hantavirus, which is a virus spread by mouse and rat feces.
A 2019 study in the journal Viruses showed people carrying the ITGB3 A2 variant (CC genotype) are less likely to get the hantavirus. In the study, none of the hantavirus patients carried two copies of the PlA2 variant. In the group exposed to the virus but who didn’t get sick, 11% of them carried two copies of the variant. This is likely not a complete protection against all hantaviruses, since the virus can use other integrin receptors in addition to ITGB3. A study of related hemorrhagic fever viruses, the ITGB3 PlA1/A2 variant was not found to be protective.[ref][ref][ref]
Covid Susceptibility and Severity: ITGB3 PlA1/A2 variants
Another virus linked to the ITGB3 variants is SARS-CoV-2. A recent study looked at genetic variants that increased or decreased the risk of getting Covid. The results showed that the ITGB3 A2 variant reduced the relative risk of getting Covid.[ref]
However, in people with the A2 variant who do catch Covid, the disease may be more severe. In the original strain of the virus, severe Covid was associated with increased prothrombotic and cardiovascular complications. The study results showed that the A2 allele was associated with an increased relative risk of severe Covid.[ref]
Related article: Covid-19 genetic susceptibility
ITGB3 PlA1/A2 Genotype Report:
Below you’ll see your genotype for the PlA1/A2 variant that mildly affects the function of ITGB3. Note that there are also rare mutations in the gene (not included here) that can cause a bleeding disorder called Glanzmann thrombasthenia.[ref]
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Lifehacks:
If you carry the A2 variant, take this as a ‘heads up’…know the signs of a blood clot and be proactive about your heart health. Talk with your doctor if you have any concerns or need medical advice.
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References:
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