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Abstract: FR-PO316

Genetic Inhibition of APOL1 Pore Forming Function Prevents APOL1 Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Hung, Adriana, VA Tennessee Valley Healthcare System, Nashville, Tennessee, United States
  • Assimon, Victoria, MAZE Therapeutics, San Francisco, California, United States
  • Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yu, Zhihong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Siew, Edward D., VA Tennessee Valley Healthcare System, Nashville, Tennessee, United States
  • Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Graham, Robert R., MAZE Therapeutics, San Francisco, California, United States
  • Hoek, Maarten, MAZE Therapeutics, San Francisco, California, United States
  • Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Green, Eric, MAZE Therapeutics, San Francisco, California, United States
  • Bick, Alexander, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Group or Team Name

  • Million Veteran Program
Background

African Americans are at increased risk for non-diabetic chronic kidney disease (CKD) in part due to high-risk variants in the apolipoprotein L1 (APOL1) gene.

Methods

We tested whether a different APOL1 variant, p.N264K, modified the association between APOL1 high-risk variants and CKD in cross-sectional analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). We replicated our analyses in the Vanderbilt BioVU Biobank (n=14,386). The co-primary outcomes were CKD and end stage kidney disease (ESKD) among non-diabetic patients. We expressed APOL1 high-risk mutations with and without APOL1 p.N264K in podocytes to study mechanisms of action.

Results

In the MVP cohort, 15,604 (12.8%) had two APOL1 high-risk mutations, of these 582 (0.5%) also had APOL1 p.N264K. In the MVP cohort, 18,831 (15%) had CKD, 4,177 (3%) had ESKD and 34% had diabetes. APOL1 high-risk variants were associated with an increased odds of CKD (odds ratio [OR] 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR 3.94; 95% CI, 3.52 to 4.41). APOL1 p.N264K mitigated the risk of APOL1 high-risk variations in CKD (OR 0.70; 95% CI, 0.45 to 1.08, interaction p=0.001) and ESKD (OR 0.73; 95% CI, 0.27 to 1.96, interaction p=0.003) (Figure 1). APOL1 p.N264K risk mitigation was replicated in BioVU. In mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and reduced toxicity of APOL1 high-risk mutations in podocytes.

Conclusion

APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 high-risk variants.

Figure 1. Association of APOL1 high-risk and p.N264K allele with end-stage kidney disease among MVP participants

Funding

  • Veterans Affairs Support