Kidney Week

Abstract: PO1326

The Kidney Genome Atlas: A Resource to Understand APOL1 and Other Genetic Drivers of Adult Proteinuric Kidney Diseases

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Fast, Eva, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Eva Fast, PhD

• Soare, Thomas, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Thomas Soare,

• Somineni, Hari, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Hari Somineni,

• Watkins, James, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

James Watkins,

• Tebbe, Adam, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Adam Tebbe,

• Lalioti, Maria, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Maria Lalioti,

• Walsh, Liron, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Liron Walsh,

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler,

• Nadkarni, Girish N., Mount Sinai Health System, New York, New York, United States

Girish N. Nadkarni,

• Gbadegesin, Rasheed A., Duke University School of Medicine, Durham, North Carolina, United States

Rasheed A. Gbadegesin,

• Wenke, Jamie L., Nashville Biosciences, Nashville, Tennessee, United States

Jamie L. Wenke,

• Macarthur, Daniel G., Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

Daniel G. Macarthur,

• Mundel, Peter H., Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Peter H. Mundel,

• Tibbitts, Thomas T., Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Thomas T. Tibbitts,

• Penny, Michelle, Goldfinch Bio Inc, Cambridge, Massachusetts, United States

Michelle Penny,

Background

Chronic kidney disease (CKD) affects more than 30 million people in the US with African Americans being particularly at risk. There is an unmet need for pharmaceutical therapies that extend or, ideally, restore kidney function.

Methods

To guide genetically-driven drug development, we have established the Kidney Genome Atlas (KGA), which contains whole-genome sequences (>30X) from adult patients with Focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and other, idiopathic, proteinuric disorders as well as public and technically matched controls. By implementing a rigorous quality control procedure, following the gnomAD pipeline, we obtained a high-confidence dataset for downstream analyses. Three genetically inferred ancestries (EUR, AFR, AMR) were included in association testing comparing 1400 cases, including 169 individuals with APOL1 G1/G1, G2/G2 or G1/G2 high risk haplotypes (APOL1-HRH), with 14686 controls (including 485 APOL1-HRH individuals).

Results

Overall, our common variant cross-ancestry meta-analysis showed minimal impact of potential confounders, such as ancestry or sequencing center differences (lambda=1.03). Using summary statistics from our EUR analysis, we estimated a SNP heritability of 0.15 (SE = 0.028) in proteinuric diseases. Comparison to a recent CKD GWAS (Wuttke et al., 2019) indicated a weak positive genetic correlation (rg) of 0.097 (SE = 0.053).
We identified the previously reported significant disease association of APOL1-HRH (p=2x10^-10) in our study. Recent in vitro data suggests amino acid in position 150 (rs2239785) is critical for the pathogenicity of APOL1-HRH (PO1986, ASN 2020) which we confirmed in our cohort of AFR ancestry individuals.

Conclusion

We have built a high-quality, multiethnic cohort that enables understanding of genetic drivers of polygenic proteinuric kidney disease. Future analysis including genetic modifiers of APOL1 may provide opportunities for novel therapies and patient stratification.

Funding

• Commercial Support –