Abstract: TH-PO0648
APOL1 High Risk Variants Associated with CKD Progression in People with Diabetes
Session Information
- Genetic Diseases of the Kidneys: Complex Kidney Traits
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- Mozaffari, Sahar V., Maze Therapeutics Inc, South San Francisco, California, United States
- Xiao, Yonghong, Maze Therapeutics Inc, South San Francisco, California, United States
- Assimon, Victoria, Maze Therapeutics Inc, South San Francisco, California, United States
- Hoek, Maarten, Maze Therapeutics Inc, South San Francisco, California, United States
- Graham, Robert R., Maze Therapeutics Inc, South San Francisco, California, United States
- Limb, Susan, Maze Therapeutics Inc, South San Francisco, California, United States
- Estrada, Karol, Maze Therapeutics Inc, South San Francisco, California, United States
Background
Genetic variants of apolipoprotein L1 (APOL1) are associated with an increased risk of chronic kidney disease (CKD) and disease progression in individuals of African ancestry. Although diabetes is a major cause of end stage renal disease (ESRD) in African Americans, the APOL1 high risk alleles have not previously been associated with diabetic kidney disease. A previous study evaluating the effects of APOL1 variants in CKD in CRIC (Chronic Renal Insufficiency Cohort), showed that black patients in the APOL1 high-risk group had a more rapid eGFR decline and a higher risk of the composite renal outcome than did white patients, among those with and without diabetes. We expand this analysis of disease progression in individuals with and without diabetes to the range of APOL1 genotypes.
Methods
We examined the CRIC cohort using almost double the longitudinal data compared to previous analyses (15 vs 8 years). Of the 2987 individuals in our analysis, 1508 were white individuals, 1194 black APOL1 low risk variant carriers, and 285 black APOL1 high risk variant carriers. Low risk variant carriers were defined as homozygous or heterozygous for G0; and high risk as carrying G1 and G2, or homozygous for either G1 or G2. We fit a Cox proportional hazards survival model to ESRD or 50% eGFR decline adjusting for age, sex, clinical site, baseline eGFR, socioeconomic variables, clinical risk factors (systolic BP, BMI, HbA1c, and smoking status), and 24 hour urinary protein to creatinine ratio. To understand difference in progression among those with and without diabetes we fit the same model in those with diabetes and without diabetes in only black individuals.
Results
We find that CKD progression was increased in black vs white patients (HR=1.66, p <0.001), and even faster in black APOL1 high risk patients (HR=2.37, p<0.001). APOL1 high risk variants had a significant effect on CKD progression in those with diabetes (HR=1.52, p=0.002) and was not significant but trending in those without diabetes (HR=1.27, p=0.098).
Conclusion
Using longer follow up in the CRIC cohort we have been able to reproduce and expand on previous findings that APOL1 high risk variant carriers have faster CKD progression overall and in those with diabetes. Our results provide a rationale for APOL1 inhibition in both non-diabetic and diabetic kidney disease.
Funding
- Commercial Support – Maze Therapeutics