Say that you slip with the knife while cutting up an apple for lunch. Ouch! It may bleed a bit, but you know that pretty soon it will stop. The physiological trick here is to ensure the clotting isn’t too quick. If clotting occurs faster or thicker than it should, the risk of clots in our vessels increases.
The ITGB3 Gene – PIA1/A2 mutation
A whole cascade of events takes place to form a blood clot. The ITGB3 gene codes for the fibrinogen receptor that is a part of how platelets form clots. The fibrinogen is the protein activated to create the fibers that shore up the clot.
The clotting action is vitally important when you cut yourself — but clotting too much or too quickly can also be a problem. Blood clots can cause heart attacks and strokes. And blood clots that form in the large veins of the leg or arm can cause deep vein thrombosis.
Does the PIA1/A2 variant increase cardiovascular event risk?
Hundreds of studies have been done on the ITGB3 genetic variant known as PIA1/A2. Here is an overview of some of the findings:
- A study of 80 men, aged 20-25 years, found that those who carry the A2 variant had faster blood clotting times. The study also found that many (but not all) of the variant carriers were also resistant to the blood-thinning effects of aspirin.[ref]
- Women carrying the variant were at an increased risk of having recurrent miscarriages.[ref]
- A study of men who died of sudden cardiac death found that the A2 variant more than doubled the risk of sudden cardiac death under the age of 50.[ref]
- The results of one study that included both men and women found only women who carried the A2 variant were at a higher risk of deep venous thrombosis.[ref]
- An overall meta-analysis combining the data from 14 studies concluded a statistical increase in the risk of heart attacks exists. This wasn’t a big increase in risk for the overall population (8%), but it had a slightly bigger impact on people younger than age 45 (a 20% increase in risk). Keep in mind, though, that the risk of heart attack is low in people younger than 45.[ref]
- Researchers looked at 1,202 Caucasian patients in an atherosclerosis study and found 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]
- A study of male physicians found carrying the A2 variant did not increase the risk of stroke, heart attack, or DVT.[ref]
While this genetic variant does seem to increase the overall risk for various cardiovascular events, keep in mind it is probably acting together with lifestyle factors and other genetic variants.
Protection from the hantavirus:
Most genetic variants that have a downside also have a positive one. There is a reason the variant survives in the population. Tradeoffs.
The downside of the A2 variant is obvious – increased early heart attack deaths, especially without modern medical care.
If all people carrying this ITGB3 gene variant died from early heart attacks, at some point the variant should have dwindled out in the human population. But, balancing the negative is a positive reason the variant still is found in the population. Research shows the variant offers protection from dying from pathogens that cause excessive bleeding.
For example, carriers of the A2 variant are protected from getting the hantavirus. The spreading of hantavirus occurs from mouse and rat feces, and, in Chile, it has a mortality rate of 30-35%.
The hantavirus causes cardiopulmonary responses due to increased vascular permeability. The study found that those people carrying the A2 variant were less likely to get the hantavirus. The study looked at who got the virus and at people exposed to the virus who didn’t get it. None of the hantavirus patients carried two copies of the PIA2 variant. In the group exposed to the virus but who didn’t get sick, 11% of them carried two copies of the variant.[ref]
While you may be thinking that the hantavirus is a new, recently discovered pathogen, historical records show that the English Sweating sickness had similar patterns and symptoms. The English Sweat is first recorded in the time of Henry VIII, with recurrences periodically over the next century or two. The timeline, conditions, death rate, and symptoms fit with hantavirus spread by rodents. Additionally, outbreaks of similar symptoms periodically spread across Europe and Russia in years with similar weather patterns. [ref]
PIA1/A2 Genetic Variant:
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Check your genetic data for rs5918 (23andMe v4, v5; AncestryDNA):
- C/C: two copies of the A2 variant, increased risk of heart disease, may not benefit from aspirin for heart attack prevention, protection against Hantavirus[ref][ref][ref]
- C/T: somewhat increased risk of heart disease, may not benefit as much from aspirin for heart attack prevention, protection against Hantavirus[ref][ref][ref]
- T/T: typical
Members: Your genotype for rs5918 is —.
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Related Articles and Genes:
Elevated Fibrinogen: Risk factor for blood clots
Fibrinogen is essential for making blood clots, but high levels of fibrinogen are linked to several health conditions. This article explains why fibrinogen levels are important and then shows you how to check your genetic data to see if you are likely to have genetically higher fibrinogen.
Prothrombin: Blood Clot Risk
Genetic variants in the prothrombin gene increase the risk of blood clots (DVTs). Learn if you carry this risk factor for miscarriage, blood clots, and stroke.
Heart Health Topic Summary
Utilize our Heart Health Topic Summary Reports with your 23andMe or AncestryDNA genetic data to see which articles may be most relevant to you. These summaries are attempting to distill the complex information down into just a few words. Please see the linked articles for details and complete references. (Member’s article)
Will Aspirin Prevent Heart Disease?
Many people take a baby aspirin every day to prevent heart disease. This is based on large-scale group studies that show that aspirin reduces heart attacks. But… we are all different, and newer research shows that not everyone benefits the same way from aspirin therapy.
Floyd, Christopher N., et al. “The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Myocardial Infarction: A Meta-Analysis.” PLOS ONE, vol. 9, no. 7, July 2014, p. e101518. PLoS Journals, https://doi.org/10.1371/journal.pone.0101518.
Ivanov, Petar D., et al. “Polymorphism A1/A2 in the Cell Surface Integrin Subunit Β3 and Disturbance of Implantation and Placentation in Women with Recurrent Pregnancy Loss.” Fertility and Sterility, vol. 94, no. 7, Dec. 2010, pp. 2843–45. www.fertstert.org, https://doi.org/10.1016/j.fertnstert.2010.05.015.
Khatami, Mehri, et al. “Common Rs5918 (PlA1/A2) Polymorphism in the ITGB3 Gene and Risk of Coronary Artery Disease.” Archives of Medical Sciences. Atherosclerotic Diseases, vol. 1, no. 1, Apr. 2016, pp. e9–15. PubMed Central, https://doi.org/10.5114/amsad.2016.59587.
—. “Common Rs5918 (PlA1/A2) Polymorphism in the ITGB3 Gene and Risk of Coronary Artery Disease.” Archives of Medical Sciences. Atherosclerotic Diseases, vol. 1, no. 1, Apr. 2016, pp. e9–15. PubMed Central, https://doi.org/10.5114/amsad.2016.59587.
Komsa-Penkova, Regina, et al. “Rs5918ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women.” Clinical and Applied Thrombosis/Hemostasis: Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, vol. 23, no. 6, Sept. 2017, pp. 585–95. PubMed, https://doi.org/10.1177/1076029615624778.
Kucharska-Newton, Anna M., et al. “Association of the Platelet GPIIb/IIIa Polymorphism with Atherosclerotic Plaque Morphology: The Atherosclerosis Risk in Communities (ARIC) Study.” Atherosclerosis, vol. 216, no. 1, May 2011, pp. 151–56. PubMed, https://doi.org/10.1016/j.atherosclerosis.2011.01.038.
Martínez-Valdebenito, Constanza, et al. “A Single-Nucleotide Polymorphism of ΑVβ3 Integrin Is Associated with the Andes Virus Infection Susceptibility.” Viruses, vol. 11, no. 2, Feb. 2019, p. 169. www.mdpi.com, https://doi.org/10.3390/v11020169.
Mikkelsson, Jussi, et al. “Glycoprotein IIIa PlA1/A2 Polymorphism and Sudden Cardiac Death.” Journal of the American College of Cardiology, vol. 36, no. 4, Oct. 2000, pp. 1317–23. jacc.org (Atypon), https://doi.org/10.1016/S0735-1097(00)00871-8.
Mukarram, Osama, et al. “A Study into the Genetic Basis of Aspirin Resistance in Pakistani Patients with Coronary Artery Disease.” Pakistan Journal of Pharmaceutical Sciences, vol. 29, no. 4, July 2016, pp. 1177–82.
Oliver, Kendra H., et al. “Pro32Pro33 Mutations in the Integrin Β3 PSI Domain Result in ΑIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606.” Molecular Pharmacology, vol. 85, no. 6, June 2014, pp. 921–31. PubMed, https://doi.org/10.1124/mol.114.091736.
—. “Pro32Pro33 Mutations in the Integrin Β3 PSI Domain Result in ΑIIbβ3 Priming and Enhanced Adhesion: Reversal of the Hypercoagulability Phenotype by the Src Inhibitor SKI-606.” Molecular Pharmacology, vol. 85, no. 6, June 2014, pp. 921–31. PubMed, https://doi.org/10.1124/mol.114.091736.
Ridker, P. M., et al. “PIA1/A2 Polymorphism of Platelet Glycoprotein IIIa and Risks of Myocardial Infarction, Stroke, and Venous Thrombosis.” Lancet (London, England), vol. 349, no. 9049, Feb. 1997, pp. 385–88. PubMed, https://doi.org/10.1016/S0140-6736(97)80010-4.
Szczeklik, Andrzej, et al. “Relationship between Bleeding Time, Aspirin and the PlA1/A2 Polymorphism of Platelet Glycoprotein IIIa.” British Journal of Haematology, vol. 110, no. 4, 2000, pp. 965–67. Wiley Online Library, https://doi.org/10.1046/j.1365-2141.2000.02267.x.
Undas, A., et al. “Pl(A2) Polymorphism of Beta(3) Integrins Is Associated with Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury.” Circulation, vol. 104, no. 22, Nov. 2001, pp. 2666–72. PubMed, https://doi.org/10.1161/hc4701.099787.
—. “Pl(A2) Polymorphism of Beta(3) Integrins Is Associated with Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury.” Circulation, vol. 104, no. 22, Nov. 2001, pp. 2666–72. PubMed, https://doi.org/10.1161/hc4701.099787.
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.