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Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant
Elena Martinelli1, Juntao Ke1, Atlas Khan1
1Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York.
Importance:
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.
Objective:
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.
Design, Setting, And Participants:
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:
Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry.
Main Outcome And Measure:
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).
Results:
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.
Conclusions And Relevance:
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.
Insights
The APOL1 M1 variant offers protection against APOL1-associated kidney diseases like focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). Individuals with high-risk APOL1 genotypes and the M1 variant should be assessed for alternative causes of their kidney disease.
Area of Science:
- Nephrology
- Genetics
- Epidemiology
Background:
- The APOL1 gene is a significant risk factor for chronic kidney disease (CKD), particularly in individuals of African ancestry.
- The M1 (p.N264K) variant of APOL1 has been shown to protect against G2-associated focal segmental glomerulosclerosis (FSGS) and CKD.
- The clinical utility of M1 variant status in diagnosing kidney diseases remains unclear.
Purpose of the Study:
- To determine if the M1 variant can differentiate APOL1-related CKD from non-APOL1 CKD in patients with high-risk (HR) APOL1 genotypes and at least one G2 allele.
- To investigate whether the M1 variant independently protects against FSGS and CKD in individuals with low-risk (LR) APOL1 genotypes.
Main Methods:
- A retrospective case-control study was conducted using data from tertiary care hospitals and large population-based biobanks (UK Biobank, eMERGE-III, All of Us).
- The study included over 107,000 individuals with diagnoses of FSGS, steroid-resistant nephrotic syndrome (SRNS), CKD, or no kidney disease.
- The presence of the M1 variant (p.N264K) was determined from exome or genome sequencing data, and its association with kidney disease status was analyzed using odds ratios.
Main Results:
- In the APOL1-HR group, the M1 variant was significantly associated with protection against FSGS or SRNS (OR, 0.20; P = 3.69 × 10-3).
- Among individuals with APOL1-HR genotypes and CKD, the M1 variant was more frequent in those whose CKD was not attributed to FSGS or SRNS.
- Medical records and biopsy reviews indicated alternative, non-APOL1 causes for CKD in nearly all APOL1-HR-M1 cases. No protective association was found for M1 in individuals with APOL1-LR genotypes.
Conclusions:
- The APOL1 M1 variant acts as a significant genetic modifier, conferring protection against APOL1-associated kidney diseases.
- For patients with CKD, an APOL1-HR genotype, and the M1 variant, further evaluation for alternative, potentially treatable causes of CKD is warranted.
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