# Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant

## TL;DR

This study shows that the M1 variant in APOL1 can help distinguish APOL1-related kidney disease from other types, suggesting a potentially treatable cause.

## Contribution

The study demonstrates that the M1 variant acts as a genetic modifier in APOL1-related kidney disease, improving diagnostic precision.

## Key findings

- The M1 variant is inversely associated with FSGS/SRNS in individuals with APOL1 high-risk genotypes.
- APOL1-HR individuals with M1 are four times more likely to have non-APOL1 CKD.
- M1 presence in APOL1-HR CKD cases is linked to alternative, treatable causes identified via medical records and biopsies.

## Abstract

This case-control study evaluates whether, in patients with APOL1 high-risk genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 chronic kidney disease from non-APOL1 chronic kidney disease.

What is the association of the protective APOL1 M1 (p.N264K) variant with kidney disease risk in individuals with APOL1 high-risk (APOL1-HR) and low-risk (APOL1-LR) genotypes?

In this case-control study of 107 696 individuals, the M1 variant was associated with improved diagnostic precision for kidney disease causes among individuals with APOL1-HR genotypes and showed no independent association with protection in the general population of individuals with APOL1-LR genotypes.

These findings suggest that presence of the M1 variant in individuals with APOL1-HR genotypes may point to a distinct and potentially actionable mechanism of kidney disease.

The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual’s M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored.

To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD.

Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls.

Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry.

The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non–kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs).

A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10−3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS.

In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.