Why These "African-Centric" Genetic Variants Don't Protect Against Malaria
For thousands of years, malaria has been one of humanity's most formidable adversaries. The deadly selective pressure of Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has literally reshaped the human genome in regions where the disease is endemic. This evolutionary arms race has favored genetic variants that provide survival advantages—even when those same variants cause diseases like sickle cell anemia in individuals who inherit two copies.
The protection offered by a single sickle cell variant against severe malaria represents perhaps the most famous example of what scientists call "the malaria hypothesis"—the concept that infectious disease can drive the evolution of protective genetic traits within populations 4 .
Against this backdrop, scientists have recently turned their attention to another genetic candidate: TP53, a gene often called the "guardian of the genome" for its crucial role in preventing cancer. Specifically, researchers investigated whether two natural variations of this gene—dubbed the "African-centric" S47 and P72 variants—might provide protection against malaria 1 2 .
To understand why scientists would investigate a cancer-related gene in malaria research, we first need to appreciate the multifaceted nature of the p53 protein. While indeed famous for its ability to prevent uncontrolled cell division and trigger programmed cell death in potentially cancerous cells, p53 plays additional roles in the body's defense systems.
Recent research has revealed that p53 is involved in regulating inflammatory responses to infections, including malaria 6 . Our immune system walks a delicate tightrope when confronting pathogens—it must mount a response vigorous enough to eliminate the invader without causing excessive collateral damage to our own tissues through uncontrolled inflammation. p53 appears to help maintain this balance.
In 2019, a pivotal study discovered that increased p53 activity in blood cells could predict whether children infected with malaria would develop fever or remain asymptomatic 6 . When researchers experimentally increased p53 levels in human immune cells and in mice, they observed a noticeable decrease in malaria-induced inflammation. This suggested that beyond its cancer-fighting capabilities, p53 might serve as a natural inflammation dampener during infections 6 .
Geneticists have identified millions of natural variations in the human genome, but most have no discernible effect on our health or survival. The variations at codons 47 and 72 of the TP53 gene, however, are different—they change the structure and function of the p53 protein in ways that could potentially influence how we respond to infections.
Genetic Change: Proline (P) → Serine (S) at position 47
Population Frequency: 2-4% in African populations
Functional Effect: Confers resistance to iron-dependent cell death (ferroptosis), which affects how cells handle iron accumulation and respond to inflammatory substances like hemozoin—a pigment released by malaria parasites 2 .
Genetic Change: Arginine (R) → Proline (P) at position 72
Population Frequency: More common in individuals of African descent
Functional Effect: Differs in its ability to trigger apoptosis (programmed cell death), which is significant because apoptosis represents one mechanism by which the host can eliminate malaria-infected liver cells 2 .
To determine whether these p53 variants actually influence malaria risk, an international team of researchers conducted a carefully designed prospective cohort study in Kalifabougou, Mali, where malaria transmission is intense and seasonal, typically occurring from June through December 2 .
The study enrolled 631 healthy Malian children and adults aged from 3 months to 25 years. These participants were then followed with biweekly active surveillance for malaria during the high-transmission season, complemented by weekly check-ups and a self-referral clinic for anyone experiencing fever symptoms 1 2 .
The researchers established clear criteria for identifying malaria cases:
The team sequenced exon 4 of the TP53 gene for all participants—this specific region of the gene contains the instructions for both the 47 and 72 codons. Using standard Sanger sequencing methods, they determined which variants each participant carried at these positions 2 .
631 healthy Malian children and adults
TP53 exon 4 analysis for S47 and P72 variants
Biweekly monitoring during high-transmission season
Statistical models to assess malaria risk associations
| Characteristic | Overall Cohort (n=631) | With S47 Variant | With P72 Variant |
|---|---|---|---|
| Age range | 3 months - 25 years | Similar distribution | Similar distribution |
| Hemoglobin S | Balanced across groups | No significant difference | No significant difference |
| Hemoglobin C | Balanced across groups | No significant difference | No significant difference |
| Malaria risk confounders | Well-controlled | No significant difference | No significant difference |
After six months of intensive monitoring and genetic analysis, the results were clear—and surprising. Neither the S47 nor the P72 variant provided any measurable protection against malaria infection or disease 1 2 .
The researchers used sophisticated statistical models (Cox proportional hazards models) to determine whether individuals carrying either variant had different outcomes regarding:
In all cases, the answer was negative. The curves showing time to malaria infection were nearly identical between those with and without the variants. Similarly, the risk of developing fever once infected didn't differ between the groups 1 2 .
These findings held true even when the researchers accounted for other known factors that influence malaria susceptibility, such as:
The study's rigorous design and comprehensive analysis strengthen the validity of these negative findings.
| Variant | Risk of Febrile Malaria | Risk of Incident Parasitemia | Time to Fever After Parasitemia |
|---|---|---|---|
| S47 | No significant association | No significant association | No significant difference |
| P72 | No significant association | No significant association | No significant difference |
| Genetic Variant | Protective Against Malaria? | Population Frequency | Biological Mechanism |
|---|---|---|---|
| Hemoglobin S (sickle cell trait) | Yes, against severe malaria | High in malaria-endemic regions | Alters red blood cell properties, making them less hospitable to parasites |
| PIEZO1 E756del | Yes, against severe malaria | Common in Africans | Increases red blood cell dehydration, reducing parasite invasion |
| ATP2B4 haplotypes | Yes, against severe malaria | Varies by population | Decreases calcium export, increasing red cell dehydration |
| p53 S47 variant | No association found | 2-4% in Africans | Alters ferroptosis resistance, but not protective against clinical malaria |
| p53 P72 variant | No association found | More common in Africans | Alters apoptotic potential, but not protective against clinical malaria |
Conducting rigorous genetic epidemiology research requires sophisticated tools and methods. Here are some key components from the Malian study that enabled these important findings:
| Research Tool | Specific Example | Function in Study |
|---|---|---|
| DNA extraction kits | QIAamp 96 DNA Blood Kit (Qiagen) | Isolates high-quality genomic DNA from blood samples for reliable sequencing |
| PCR amplification systems | HotStarTaq Plus Master Mix Kit (Qiagen) | Amplifies specific TP53 gene regions for detailed analysis |
| DNA sequencing technologies | Sanger sequencing (Quintara Biosciences) | Determines exact genetic code at codons 47 and 72 of TP53 |
| Statistical analysis software | R software (version 4.2.0) | Provides powerful statistical methods for analyzing genetic associations with health outcomes |
| Malaria diagnostics | Microscopy + PCR of dried blood spots | Accurately detects and confirms Plasmodium falciparum infection, even at low levels |
Participants
Months of Surveillance
TP53 Variants Analyzed
The negative findings from this study actually reveal something profound about the complex nature of malaria resistance. Rather than being controlled by a few genes with large protective effects, malaria susceptibility appears to be what scientists call a "highly polygenic" trait 4 .
This means that an individual's resistance or susceptibility to malaria likely depends on the combined effect of hundreds or even thousands of genetic variations, each contributing a small effect. Recent genome-wide association studies (GWAS) have confirmed this view, identifying five genome-wide significant variants that collectively explain only about 11% of the heritability of severe malaria risk 4 .
The fact that the p53 variants showed no protective effect reminds us that not every geographical pattern in genetic distribution has a simple explanation related to infectious disease resistance. While the "malaria hypothesis" beautifully explains the distribution of variants like sickle cell trait, it doesn't apply to every genetic variant that happens to be more common in malaria-endemic regions 4 .
Known protective variants
Unknown factors
In science, negative results—those that disprove rather than confirm hypotheses—are often undervalued, yet they play a crucial role in advancing our understanding. This carefully conducted study demonstrating no protective effect of p53 S47 and P72 variants against malaria represents exactly this type of scientifically valuable work.
These findings help redirect scientific attention toward the complex polygenic nature of malaria resistance and away from what might otherwise seem like obvious candidate genes 4 . They remind us that the human genome tells a complicated story of evolutionary adaptation—one that can't be reduced to simple narratives about single genes and single diseases.
As research continues, scientists will keep unraveling the intricate genetic orchestra that contributes to malaria resistance, building on both positive and negative findings to paint a more complete picture of how this ancient disease has shaped us, and how we might better protect future generations from its impact.
Acknowledgments: The research highlighted in this article was conducted by an international team of scientists in Mali and published in the Journal of Infectious Diseases. The study was approved by relevant ethical review boards in Mali and at the National Institutes of Health.