Abstract: TH-OR82
Enhanced Diagnostic Precision in APOL1-Mediated Kidney Disease with the p.N264K M1 Protective Variant
Session Information
- Non-Cystic Genetic Kidney Diseases: Disease Genes, Modifiers, and Therapies
October 24, 2024 | Location: Room 23, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Martinelli, Elena, Columbia University, Division of Nephrology, New York, United States
- Ke, Juntao, Columbia University, Division of Nephrology, New York, New York, United States
- Khan, Atlas, Columbia University, Division of Nephrology, New York, New York, United States
- Vanderwall, David R., Division of Nephrology, Boston Children Hospital, Boston, Massachusetts, United States
- Wongboonsin, Janewit, Renal division, Brigham and Women’s Hospital, Boston, United States
- Lim, Tze Yin, Columbia University, Division of Nephrology, New York, New York, United States
- Saleem, Moin A., Division of Pediatric Nephrology, University of Bristol, Bristol, United Kingdom
- Gbadegesin, Rasheed A., Division of Pediatric Nephrology, Duke University, Durham, North Carolina, United States
- Hildebrandt, Friedhelm, Division of Nephrology, Boston Children Hospital, Boston, Massachusetts, United States
- Gharavi, Ali G., Columbia University, Division of Nephrology, New York, New York, United States
- Kiryluk, Krzysztof, Columbia University, Division of Nephrology, New York, New York, United States
- Sampson, Matt G., Division of Nephrology, Boston Children Hospital, Boston, Massachusetts, United States
- Pollak, Martin, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University, Division of Nephrology, New York, New York, United States
Background
The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 kidney disease. Utilization of this knowledge can potentially inform precise diagnosis in individuals with APOL1 high-risk (HR) genotypes (G1/G2, G2/G2). Here we tested two hypotheses: (I) in APOL1-HR individuals, M1 genotyping can help in guiding accurate diagnosis of APOL1 kidney disease or non APOL1 CKD; (II) in APOL1 low-risk (LR), M1 might confer an independent protective effect against FSGS and kidney disease.
Methods
We analyzed exome/genome sequencing data from 118,749 individuals with: FSGS or steroid resistant nephrotic syndrome (SRNS) (N= 3,464), kidney disease non FSGS/SRNS (N= 28,475), and non-kidney disease controls (N=86,810). We extracted G1 and G2 genotypes to infer APOL1 HR and LR genotypes, and rs73885316 (p.N264K) to infer M1 prevalence in these groups. Pairwise M1 carrier prevalence comparisons were conducted across categories by Fisher’s exact test.
Results
In the APOL1-HR (N=1,590), M1 was, as expected, significantly depleted in FSGS/SRNS cases (0.63%) compared to non-kidney disease controls (4.14%; P=1.3 x 10-4; OR=0.15, 95%CI 0.02-0.58), driven by APOL1 G2-containing genotypes. CKD non FSGS/SRNS cases were 4-fold more likely to harbor M1 as compared to FSGS/SRNS cases. Chart review identified an alternative, non APOL1, cause for CKD (autoimmune, structural, metabolic, cystic, or al) in all APOL1-HR-M1 cases. Conversely, in APOL1-LR individuals, we detected no protective effect of M1 for FSGS/SRNS.
Conclusion
We did not detect an independent protective effect of M1 in the absence of APOL1-HR genotypes, consistent with its role as a genetic modifier. In APOL1-HR individuals, M1 enhanced diagnostic precision and can help identify cases with an alternative and potentially treatable cause of CKD not driven by APOL1. Given the prevalence of M1 carriers in CKD, we estimate that at least 1 in 23 individuals who carry a G2-containing APOL1-HR genotype do not have APOL1 kidney disease or FSGS.
Funding
- NIDDK Support