The presence of the M1 genetic variant may confer protection in people with high-risk, APOL1-associated kidney disease, who are predominantly of Black African ancestry, with potentially important implications for diagnosis and treatment, according to new research.

“These results reinforce the knowledge that APOL1 genetic testing is incomplete without reporting M1 status,” said first author Elena Martinelli, MD, a postdoctoral research fellow at Vagelos College of Physicians and Surgeons, Columbia University, in New York City, in a press statement.

Importantly, “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, non-APOL1 — potentially treatable — causes of kidney disease, rather than assuming that APOL1 is responsible,” added senior author Simone Sanna-Cherci, MD, associate professor of medicine at Columbia University.

The study was published in JAMA Network Open.

At-Risk Populations

Black Americans have a risk for kidney disease up to five times higher than individuals of European ancestry. Although APOL1 variants are linked to this increased risk, only about 13% of Black individuals carry high-risk genotypes.

Even among those with high-risk APOL1 variants, distinguished by the presence of the G2 genotype associated with kidney damage, only a small subset develop APOL1-associated kidney disease. Ongoing research has focused on identifying modifiers that influence this risk.

In a previous study, the authors found that among carriers of high-risk G2 APOL1 genotypes, the presence of M1 was protective, “virtually negating” kidney disease risk and “effectively rendering G2-containing APOL1 [high-risk] genotypes comparable with non-risk genotypes.”

Retrospective Case-Control Analysis

To explore whether M1 had a similarly protective association in individuals with low-risk APOL1 genotypes, the authors conducted a retrospective case-control study using data from 107,696 individuals in two large hospital biobanks, Columbia University Irving Medical Center and Mass General Brigham health system.

The findings were validated in an additional 23,955 individuals of African ancestry from the Electronic Medical Records and Genomics project, the UK Biobank, and the All of Us research program.

Among those carrying APOL1 high-risk variants (n = 1413), the presence of M1 was associated with a substantially lower risk for focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome, than those with APOL1 but without kidney disease (odds ratio, 0.20).

Notably, in nearly all patients with APOL1-high risk genotypes who carried M1, chronic kidney disease was attributed to other causes than APOL1.

In contrast, among individuals with low-risk APOL1 genotypes, M1 did not confer protection against chronic kidney disease or focal segmental glomerulosclerosis.

“This finding is consistent with the role of the M1 variant as a genetic modifier that exclusively neutralizes the deleterious effects of G2, without independently preventing non-APOL1 kidney disease,” the authors wrote.

Impact on Genetic Testing

The findings have growing clinical relevance as APOL1 genetic testing becomes more widely available.

As a result, “the risk of misdiagnosis, with consequent inadequate management and therapy, is real,” Martinelli noted. “It’s important to realize that even if a person with kidney disease has a high-risk APOL1 genotype, those variants are not always the cause of the disease.”

The authors noted that most sequencing panels already capture M1, making it feasible to easily incorporate into routine APOL1 testing.

Currently available commercial tests such as the Renasight panel include APOL1 among hundreds of kidney disease-related genes and are often covered by insurance, although out-of-pocket costs may apply.

Overall, “this study paves the way for increasingly personalized approaches to kidney disease diagnosis, management, and treatment, especially for individuals of African ancestry,” the authors concluded.

Expert Perspective

Commenting on the study, Akinlolu Ojo, MD, PhD, executive dean of the School of Medicine and professor of nephrology and hypertension at the University of Kansas Medical Center in Kansas City, Kansas, said the findings help clarify treatment implications.

“[High-risk APOL1 patients] with the M1 variant may not benefit from therapies specifically targeting APOL1,” said Ojo, who was not involved in the study.

However, he noted that the high-risk G2/G2 genotype APOL1 profile accounts for only roughly 2% of individuals with APOL1 kidney risk variants.

“That is to say that most at-risk individuals do not have the M1 genetic protective factor,” Ojo told Medscape Medical News.

“Individuals with the M1 variant are still susceptible to kidney disease from other causes that may present with clinical features similar to APOL1-mediated kidney disease,” he added.

Nevertheless, identifying M1 status could help avoid unnecessary treatments and potential complications.

“The take-home message is that clinical testing for APOL1 kidney risk variants should include testing for the M1, as the presence of M1 alters has the implications of the test results depending on the reason for testing,” Ojo said.

This study was funded by the Department of Defense, the National Institutes of Health, the University of Michigan, NephCure Kidney International, Alport Syndrome Foundation, and the Halpin Foundation. Additional author disclosures are detailed in the published study. Ojo reported having relationships with Arbor Research Collaborative for Health, AstraZeneca UK Unlimited, Regeneron Pharmaceuticals, and Vertex Pharmaceuticals Incorporated.