p.N264K (M1) Refines APOL1‑HR Diagnostic Precision

A large case-control analysis examined whether the APOL1 p.N264K (M1) variant modifies kidney disease risk among people carrying APOL1 high-risk genotypes, with a focus on focal segmental glomerulosclerosis (FSGS) and steroid-resistant nephrotic syndrome (SRNS). The authors report that, among APOL1 high-risk carriers, M1 was less common in FSGS/SRNS cases than in individuals without kidney disease, consistent with lower odds of these phenotypes when M1 is present. They also describe parallel analyses in APOL1 low-risk genotypes and a clinical record review of APOL1–high-risk, M1-positive cases identified in the discovery cohort.

The retrospective case-control discovery cohort included 107,696 individuals from Columbia University Irving Medical Center and the Mass General Brigham Biobank. Participants were categorized as having FSGS/SRNS, non-FSGS chronic kidney disease (CKD), or no evidence of CKD (controls). Within the APOL1 high-risk subgroup, the authors’ Firth bias-reduced logistic regression analysis found that the p.N264K (M1) variant was inversely associated with FSGS/SRNS vs non–kidney disease controls (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10−3). In their framing, this pattern supports M1 as a modifier that refines APOL1 high-risk genotype–associated disease risk in the studied cohort.

For external consistency, the authors report replication efforts across 3 population-scale datasets restricted to individuals of African ancestry: eMERGE-III, UK Biobank, and the All of Us research program (23,955 individuals total across these biobanks, as described). They describe direction-consistent associations between M1 and lower odds of FSGS/SRNS among APOL1 high-risk carriers, with limited statistical support in the individual biobanks and in aggregate. Using a Cochran-Mantel-Haenszel approach stratified by biobank and sex, they report a common OR of 0 (95% CI, 0.00-1.26; P = .11) for FSGS/SRNS vs controls and a common OR of 0 (95% CI, 0.00-1.73; P = .26) for FSGS/SRNS vs non-FSGS CKD; both confidence intervals cross 1 with non-significant P values, and the authors emphasize that scarce FSGS/SRNS case counts in these sources constrained precision.

In analyses of APOL1 low-risk genotypes, the article reports no evidence that M1 is independently associated with protection from FSGS/SRNS or CKD, including when analyses were restricted to genetic African ancestry and when limited to G0G0. The authors also conducted retrospective record review among APOL1 high-risk, M1-positive CKD cases in the discovery cohort: they report identifying an alternative, non-APOL1 cause for CKD in 10 of 13 reviewed non-FSGS CKD cases, and they describe both reviewed APOL1 high-risk, M1-positive FSGS/SRNS cases as having presentations suggesting non-APOL1 mechanisms. In this reviewed subset, these observations were presented as frequent co-occurrence of APOL1 high-risk genotypes with M1 in clinical scenarios where non-APOL1 explanations were often documented.

The discussion also highlights interpretive and classification considerations related to M1 status. The authors describe concern that APOL1 high-risk genotypes can be over-attributed as an explanation for CKD given incomplete penetrance, and they note the emergence of a dedicated ICD-10 code (N07.B) for APOL1 kidney disease as a context where diagnostic assignment may be affected by improved genetic resolution. They also discuss potential downstream implications of M1 status for interpreting APOL1 results, including in transplant settings and for risk assessment/stratification in APOL1-targeted therapeutic studies, while characterizing M1 as acting primarily as a modifier of G2-associated risk. They further state that many testing workflows use sequencing-based panels in which M1 is already captured, positioning reporting practices—rather than assay redesign—as a key operational issue within their framing.

Key Takeaways:

• Among APOL1 high-risk carriers, the authors report an inverse association between M1 and FSGS/SRNS compared with non–kidney disease controls.
• In APOL1 low-risk genotypes, the article reports no independent protective association of M1 for FSGS/SRNS or CKD.
• In a reviewed subset of APOL1 high-risk, M1-positive CKD cases, the authors report that alternative (non-APOL1) etiologies were documented in most records examined.