The ACE2 Gene and COVID-19
Why Your Unique DNA Isn't The Whole Story
The key to understanding our individual fight against COVID-19 may lie in our genes, but the reality is more complex than we imagined.
Imagine the SARS-CoV-2 virus as a spaceship trying to dock with a space station. That docking station on our cells is a protein called ACE2 (Angiotensin-Converting Enzyme 2). Whether the virus successfully docks—and how well—might depend on the exact molecular structure of your personal ACE2 station, which varies from person to person due to genetic differences.
Scientists worldwide have raced to answer a crucial question: Could naturally occurring variations in the ACE2 gene make some people more susceptible to severe COVID-19? The emerging answer is both fascinating and reassuring.
The Gateway to Our Cells
To understand why ACE2 is so important, we need to look at its dual role in our body. This protein is not just a viral gateway; it plays a critical part in regulating our blood pressure, inflammation, and overall cardiovascular health .
ACE2 Dual Function
Viral Entry Point
Serves as the primary receptor for SARS-CoV-2 cellular entry
Cardiovascular Regulation
Balances blood pressure and reduces inflammation
The ACE2 protein acts as a crucial balancing force in the Renin-Angiotensin System (RAS), which controls blood pressure and fluid balance. It works by converting angiotensin II, a protein that raises blood pressure and promotes inflammation, into angiotensin-(1-7), which has protective effects 4 .
When SARS-CoV-2 binds to ACE2, it does more than just gain entry to cells—it can trigger the downregulation of this protective enzyme, potentially tipping the balance toward increased inflammation and tissue damage 4 .
The Genetic Investigation Begins
Early in the pandemic, scientists hypothesized that natural genetic variations in the ACE2 gene might be a key factor in determining why some people experienced severe COVID-19 while others had mild or no symptoms. These genetic differences, known as missense variants, change single amino acids in the ACE2 protein and could theoretically affect how the virus binds to our cells 7 9 .
Genetic Variation Impact
Missense variants change single amino acids in the ACE2 protein structure
Research Focus
Scientists examined how these variants affect viral binding and protein function
Researchers identified several potential mechanisms through which ACE2 variants could influence COVID-19 severity:
The scientific community launched numerous studies to investigate these possibilities, with one comprehensive examination standing out in its thorough approach.
Inside the Lab: Tracing ACE2 Variants
A team of researchers undertook a systematic investigation to answer a fundamental question: Do naturally occurring missense variants in ACE2 affect its ability to reach the cell surface where SARS-CoV-2 enters? 7
The Experimental Blueprint
Their methodology was both meticulous and comprehensive:
Variant Selection
Researchers selected 28 different missense variants distributed across all domains of the ACE2 receptor, identified from genetic databases as naturally occurring in human populations 7 .
Computer Modeling
Before laboratory experiments, they used multiple bioinformatics tools (SIFT, PolyPhen-2, PROVEAN) to predict which variants might be damaging to the protein's function 7 .
Protein Modeling
Scientists generated three-dimensional models of the mutant proteins to visualize potential structural changes 7 .
Laboratory Verification
Using site-directed mutagenesis, they created each variant in human ACE2 plasmids, then transfected them into cells to observe the protein's journey 7 .
Trafficking Analysis
Through sophisticated imaging techniques, the team tracked whether each ACE2 variant successfully reached its proper destination at the plasma membrane or got stuck somewhere along the secretory pathway 7 .
The experimental workflow moved from computational predictions to laboratory validation, providing a comprehensive assessment of how these variants behave in actual human cells.
Selected ACE2 Missense Variants and Their Predicted Effects
| Variant | Global Allele Frequency | Computational Prediction | Experimental Result |
|---|---|---|---|
| R768W | Very Low | Deleterious | Normal Trafficking |
| G575V | Very Low | Deleterious | Normal Trafficking |
| G173S | Very Low | Deleterious | Normal Trafficking |
| D785N | Very Low | Tolerated | Normal Trafficking |
| I727V | Very Low | Tolerated | Normal Trafficking |
Surprising Results and Their Meaning
The findings challenged many expectations. Among the 28 variants tested—including three (R768W, G575V, and G173S) predicted to be deleterious by computational tools—none showed significant disruption to ACE2 trafficking or its ability to reach the cell surface 7 .
This was particularly surprising because similar mutations in related proteins (like the Q1069R mutation in the ACE protein) are known to cause retention in the endoplasmic reticulum, preventing the protein from reaching its functional location 7 .
The research team extended their investigation to examine potential effects on N-glycosylation—a crucial modification process that proteins undergo during their maturation. Again, they found no notable differences between the variants and the normal ACE2 protein 7 .
The Bigger Picture: ACE2 Variants in Context
This detailed investigation helps explain broader observations across multiple studies. While initial concerns focused on how ACE2 variations might affect SARS-CoV-2 binding, the evidence suggests that most naturally occurring ACE2 variants are extremely rare and have minimal impact on COVID-19 susceptibility 7 .
Deep Mutational Learning
Other research approaches have reached similar conclusions. Studies using deep mutational learning have focused primarily on mutations in the viral spike protein rather than human ACE2 variants when predicting changes in binding affinity 5 .
Structural Analysis
Structural analyses of ACE2 variants have revealed why most changes have little effect: the critical virus-binding interface of ACE2 appears evolutionarily constrained 7 .
Why Most ACE2 Variants Don't Affect SARS-CoV-2 Binding
| Factor | Explanation | Impact |
|---|---|---|
| Evolutionary Constraint | The ACE2 protein has essential physiological functions in regulating blood pressure and cardiovascular health | Mutations that significantly alter the spike-binding interface are rarely tolerated in evolution |
| Low Frequency | Potentially impactful variants occur at extremely low frequencies in populations | Limited opportunity to observe significant effects in clinical studies |
| Structural Stability | Most variants don't affect the overall folding or trafficking of the protein | ACE2 reaches the cell surface normally regardless of these variations |
| Binding Site Conservation | The critical virus-binding region is structurally robust to minor changes | Viral docking capability remains largely unchanged |
The Scientist's Toolkit: Decoding ACE2
Understanding how researchers study ACE2 and its variants reveals the sophistication of modern molecular medicine:
Essential Tools for ACE2 Research
| Research Tool | Function in ACE2 Research |
|---|---|
| Site-Directed Mutagenesis | Precisely introduces specific genetic variations into the ACE2 gene to create defined missense variants for study 7 |
| Computational Prediction Tools (SIFT, PolyPhen-2) | Algorithms that analyze protein sequences to predict whether genetic variants will be functionally damaging 7 |
| Homology Modeling | Creates three-dimensional models of ACE2 variants based on the known structure of the normal protein 7 |
| Yeast Surface Display | Allows high-throughput screening of how thousands of different mutations affect ACE2 binding to the viral spike protein 5 |
| Deep Mutational Learning | Combines experimental data with machine learning to predict the effects of mutations on ACE2 binding and antibody escape 5 |
| Single-Cell RNA Sequencing | Maps exactly which cell types express ACE2 and at what levels across different tissues |
Comparison of Research Methods in ACE2 Studies
| Method Type | Examples | Strengths | Limitations |
|---|---|---|---|
| In Silico (Computer) | SIFT, PolyPhen-2, PROVEAN 7 | Rapid analysis of many variants; low cost | Predictions require experimental validation |
| In Vitro (Laboratory) | Site-directed mutagenesis, trafficking studies 7 | Controlled conditions; direct observation | May not capture full complexity of human body |
| Hybrid Approaches | Deep mutational learning 5 | Combines scale of computing with validation of experiments | Complex implementation; requires specialized expertise |
Beyond Genetics: What Really Matters for COVID-19
If ACE2 variants aren't the primary factor in COVID-19 severity, what does matter? Research points to several more significant determinants:
Age and Sex
The age and sex of an individual strongly correlate with COVID-19 outcomes, with older individuals and males generally at higher risk for severe disease. Interestingly, these factors also correlate with natural variations in ACE2 levels, though not necessarily due to genetic differences in the ACE2 gene itself 4 .
Preexisting Conditions
Preexisting conditions like hypertension, diabetes, and cardiovascular disease remain strong predictors of severe COVID-19. These conditions often involve dysregulation of the very systems that ACE2 helps regulate, suggesting a more complex relationship than simple genetic determinism 9 .
Immunological Factors
Perhaps most importantly, immunological factors—including prior immunity from vaccination or infection, and individual differences in immune response—play a far greater role in determining COVID-19 outcomes than ACE2 genetic variations 8 .
Relative Impact of Different Factors on COVID-19 Severity
Looking Forward: Implications for Personalized Medicine
The investigation into ACE2 variants exemplifies a broader shift in personalized medicine. While initial excitement often focuses on simple genetic explanations for disease susceptibility, the reality is frequently more complex.
This research has practical implications for drug development. Rather than targeting individual genetic variations in ACE2, therapeutic efforts have shifted toward broadly applicable treatments like recombinant ACE2 proteins that can act as decoys for the virus, regardless of a person's genetic makeup .
The story of ACE2 research reminds us that in biology, simple explanations are rare. Our bodies have evolved multiple overlapping systems to maintain crucial physiological functions, and this redundancy protects us from what might otherwise be vulnerability to newly emerging threats.
As COVID-19 continues to evolve, so too does our understanding of the intricate dance between virus and host. The ACE2 protein remains a critical piece of this puzzle, but its genetic variations tell only a small part of a much larger story of human health and disease resilience.