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

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.