A Genetic Safeguard Called M1 Could Prevent Kidney Disease Misdiagnosis in Black Patients

Columbia University Irving Medical Center

Kidney disease is five times more common in Black Americans than in Americans with predominantly European ancestry. Most of that increased risk traces to a single gene: APOL1. About 13% of people with West and Central African ancestry carry high-risk versions of APOL1 that raise the odds of developing kidney disease. But here is the complication that makes clinical decisions difficult: most people who carry those high-risk variants never develop kidney disease at all.

So when a Black patient presents with chronic kidney disease and genetic testing reveals an APOL1 high-risk genotype, how does a doctor know whether APOL1 is actually the cause? A new study from Columbia University, published in JAMA Network Open, argues that a closer look at the gene itself can provide a much better answer.

The M1 variant changes the equation

The study builds on earlier research from the same group that identified a genetic safeguard within the APOL1 gene called M1 (formally APOL1 p.N264K). In patients who carry both a high-risk APOL1 genotype and the M1 variant, the protective variant appears to neutralize the harmful effects of the risk allele. The high-risk genotypes produce a protein that can damage the kidney, but M1 blocks that damage.

The new study asked a practical clinical question: can the presence of M1 help doctors determine the true cause of a patient's kidney disease? The research team, led by Simone Sanna-Cherchi, an associate professor of medicine at Columbia's Vagelos College of Physicians and Surgeons, examined health records of approximately 107,000 individuals from two large academic medical centers.

After detailed review of medical records and available biopsy data, the researchers found that nearly all patients with chronic kidney disease who carried both an APOL1 high-risk genotype and M1 did not have APOL1 kidney disease. Their kidney disease had a different cause, one that might respond to different treatments.

Three percent of high-risk patients may be misclassified

In the study cohort, approximately 3% of individuals with chronic kidney disease classified as APOL1 high-risk also carried the M1 variant. That proportion sounds small, but in the context of the large number of Black Americans undergoing APOL1 genetic testing, it represents a meaningful population of patients who may be receiving an incorrect diagnosis.

The clinical stakes are significant. Treatment for kidney disease depends on its root cause. A patient whose kidney disease is driven by APOL1 may eventually benefit from APOL1-targeted therapies now in development. A patient whose disease has a different cause needs a different workup and different treatment. Misattributing the disease to APOL1 could mean missing a treatable condition.

Sanna-Cherchi recommended that when patients with APOL1 high-risk genotypes also carry M1, clinicians should conduct a complete diagnostic workup, which might include a kidney biopsy, to evaluate for alternative causes of kidney disease rather than assuming APOL1 is responsible.

Testing infrastructure already exists

One of the study's practical strengths is that implementation would require minimal new infrastructure. Most sequencing panels used for APOL1 genetic testing already capture the M1 variant. The information is being collected but not routinely reported or used in clinical decision-making. Changing that practice could be straightforward.

First author Elena Martinelli, a postdoctoral fellow in the Sanna-Cherchi lab, emphasized the broader principle: even if a person with kidney disease has a high-risk APOL1 genotype, those variants are not always the cause. Because APOL1 risk variants are common in people of African ancestry, and APOL1 genetic testing is becoming increasingly accessible through point-of-care testing, the risk of misdiagnosis is real and growing.

Implications for clinical trials

The findings also have implications for the design of clinical trials testing APOL1-targeted therapies. If some participants in those trials actually have kidney disease from a non-APOL1 cause, they would not be expected to benefit from APOL1-directed treatment. Including them dilutes the apparent effectiveness of the therapy and makes it harder to determine whether the drug works. More precise genetic classification using M1 status could improve trial design and patient selection.

What remains unknown

The study does not identify what causes kidney disease in M1-positive, APOL1 high-risk patients. It establishes that APOL1 is likely not the culprit but does not point to the alternative diagnosis. Each patient would need an individualized workup to determine the actual cause, which could range from diabetic nephropathy to IgA nephropathy to other genetic conditions.

The research also does not explain why M1 provides protection. The mechanism by which this variant neutralizes the harmful APOL1 protein is not yet fully understood, and understanding it could inform therapeutic development.

The team plans to continue investigating additional genetic and environmental modifiers that may explain why only a subset of APOL1 high-risk individuals develop kidney disease. The answer is likely not a single modifier but a network of factors, genetic and otherwise, that collectively determine whether a high-risk genotype translates into actual disease.

For now, the actionable message is simple: APOL1 genetic testing should include M1 status, and a high-risk genotype alone should not be taken as a definitive diagnosis.