Awards

Gold Medal: iGEM 2023

Nominee: Best undergraduate diagnostics project

Overview

Cardiovascular disease is a leading cause of death worldwide and is significantly affected by medical inequity. Southeast Michigan is no exception, and Michigan iGEM is using synthetic biology to advance accessible, personalized medicine.

This year, we are developing a test which detects the presence of a genetic variant which may contribute to increased risk of thrombosis and reduced efficacy of some standard antiplatelet medications while leaving alternatives unaffected.

We hope to inform personalized care of those experiencing or at risk for cardiovascular disease, ensuring all patients are prescribed the best drug for them.

Cardiovascular Disease & Health Disparities

Cardiovascular disease (CVD) is experienced at disproportionately high rates by racial minority groups in the United States1,2. In particular, venous thromboembolism is a very common cardiovascular condition that affects different populations at shockingly disparate levels, with 30-60% higher rates in African American patients than patients of European descent.

Graphic showing CVD causes 17.9 million deaths every year and the higher rates of venous thromboembolism in Black patients.

Genetic Determinants of Cardiovascular Health

In search of ways to mitigate cardiovascular health inequity, our team has explored personalized pharmacotherapy and the pharmacogenetics affecting patient outcomes.

From literature, we identified the rs773902 single nucleotide polymorphism (SNP) as a potential thrombotic risk factor and modulator of antiplatelet prescription efficacy3.

What are Single Nucleotide Polymorphisms (SNPs)?

  • Genetic variations of single nucleotides at a specific point in a gene
  • Can sometimes alter the structure and functionality of encoded proteins
  • Alterations in protein structure and function can increase patient susceptibility to certain conditions, produce pathological effects, or cause resistance to medications
  • rs773902 SNP is located in the F2RL3 gene which codes for the PAR4 protein3
  • PAR4 is a thrombin receptor of human platelets and is involved in blood clotting
  • A single G to A difference in the codon for the 120th amino acid of PAR4 switches an alanine (PAR4-Ala120) to a threonine (PAR4-Thr120)
  • The PAR4-Thr120 variant causes PAR4 to have increased sensitivity to thrombin3
Graphic showing less than 19% of Caucasion individuals have PAR4-Thr120 variation compared to 63% of Black individuals.

This SNP is found at lower rates in white individuals than those of African descent, who were often underrepresented in historic clinical trials evaluating therapeutic efficacy, contributing to race-based medical inequity3

AntiPlatelet Therapy

Antiplatelet medications are a common prescription choice for patients after undergoing a thrombotic event.

There are several options for antiplatelet therapy. rs773902 has may increase a patient's resistance to the standard-of-care antiplatelet therapy regimen of aspirin and clopidogrel. However, the efficacy of other medications such as heparin and ticagrelor are not affected by the rs773902. While these alternatives are not the best choice for every patient, they could be reconsidered by prescribers with knowledge of a patient's genetics3.

Our Solution

We believe information regarding a patient's F2RL3 genotype may be valuable to a clinician when making personalized treatment decisions.

In order to empower physicians to make more informed antiplatelet therapy prescriptions, our team chose to develop a point-of-care platform for SNP detection.

We have designed our test to be fast, cost effective, accessible in low-resource settings, and generalizable to other SNPs.

Our Platform

Currently, clinical SNP detection is done through next generation sequencing4,5.

Genetic testing is difficult, slow, and expensive whereas the Michigan team's platform is easy, fast, and affordable.

How does our platform work?

The Michigan team's solution includes collecting, amplifying, detecting, and measuring.

What makes our test special?

Easy

LAMP can be done at a constant temperature

Affordable

Utilizes a heating block and a basic fluorescence reader instead of a costly qPCR machine

Fast

Takes less than 90 minutes

These qualities enable our test to be done in a point-of-care setting such that healthcare providers can use our platform to determine a patient's rs773902 genotype, then use this data to inform antiplatelet prescription decisions within a single visit.

Generalizability

This quick, inexpensive test enables physicians to determine prescriptions that best meet the needs of individual patients with accessible technology, ultimately reducing inequity in patient treatment outcomes.

Our system may be applied to other clinically relevant SNPs to empower physicians of any resource level to acquire critical genetic information to inform patient care.

Accessible detection of such genetic variations can empower personalized medical care to help reduce healthcare disparities.

Learn More

Learn more about how and why we did this on the different pages of our wiki.

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References

  1. Gregson, J., Kaptoge, S., Bolton, T., Pennells, L., Willeit, P., Burgess, S., Bell, S., Sweeting, M., Rimm, E.B., Kabrhel, C., Zöller, B., Assmann, G., Gudnason, V., Folsom, A.R., Arndt, V., Fletcher, A., Norman, P.E., Nordestgaard, B.G., Kitamura, A., ... Emerging Risk Factors Collaboration. (2019). Cardiovascular Risk Factors Associated With Venous Thromboembolism. JAMA Cardiol, 4(2):163-173. 10.1001/jamacardio.2018.4537. PMID: 30649175; PMCID: PMC6386140.
  2. Zakai, N. A., & McClure, L. A. (2011). Racial differences in venous thromboembolism. Journal of Thrombosis and Haemostasis, 9(10), 1877–1882. https://doi.org/10.1111/j.1538-7836.2011.04443.x
  3. Tourdot, B. E., Stoveken, H., Trumbo, D., Yeung, J., Kanthi, Y., Edelstein, L. C., Bray, P. F., Tall, G. G., & Holinstat, M. (2018). Genetic variant in human PAR (protease-activated receptor) 4 enhances thrombus formation resulting in resistance to Antiplatelet Therapeutics. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(7), 1632–1643. https://doi.org/10.1161/atvbaha.118.311112
  4. Qin, Dahui. “Next-Generation Sequencing and Its Clinical Application.” Cancer Biology & Medicine, U.S. National Library of Medicine, Feb. 2019, www.ncbi.nlm.nih.gov/pmc/articles/PMC6528456/.
  5. Genetic Testing Frequently asked questions. Massachusetts General Hospital. (n.d.-a). https://www.massgeneral.org/cancer-center/treatments-and-services/cancer-genetics/genetic-testing-frequently-asked-questions#:~:text=Most%20tests%20are%20returned%20within,results%20is%20up%20to%20you.
  6. Hyman, L. B., Christopher, C. R., & Romero, P. A. (2022). Competitive SNP-lamp probes for rapid and robust single-nucleotide polymorphism detection. Cell Reports Methods, 2(7), 100242. https://doi.org/10.1016/j.crmeth.2022.100242