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Abstract: SA-PO262

Accelerating Drug Discovery for CKD Through Mendelian Randomization Analyses of Druggable Proteins

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Guanchao, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Group or Team Name

  • Million Veteran Program.
Background

Drug repurposing can accelerate the discovery of treatments for chronic kidney disease. To identify potential therapeutic targets, we conducted Mendelian randomization analyses using genetic instruments for proteins targeted by approved drugs or drugs in clinical development.

Methods

Genetic instruments for 879 druggable proteins were derived from the Genotype-Tissue Expression (GTEx) project. Kidney outcomes included estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD), and end-stage kidney disease (ESKD) derived from genome-wide association study summary statistics of European ancestry individuals in the Million Veteran Program (MVP). A drug target was considered significant if it met study-wide Bonferroni significance in the inverse variance weighted analysis for all three kidney outcomes stratified by diabetes status. Significant findings in MVP were replicated in the Chronic Kidney Disease Genetics Consortium (CKDGen). Analysis was performed using the TwoSampeMR package in R version 3.3.3 using the Vanderbilt Advanced Computing Center for Research and Education.

Results

Our study identified 69 independent drug targets within MVP (p < 9.48E-06). Shared targets in non-diabetic patients were Myosin Heavy Chain 7B (peGFR = 8.70E-08, pCKD = 5.95E-17, pESKD = 5.80E-12) and Gonadotropin Releasing Hormone Receptor (peGFR = 3.61E-14, pCKD = 1.94E-15, pESKD = 2.07E-09, 3.24E-17). Shared targets in diabetic patients were HLA-DRB1 (peGFR = 3.31E-54, pCKD = 1.05E-53, pESKD = 1.72E-14), Glycoprotein Nmb (peGFR = 1.52E-14, pCKD = 5.37E-16, pESKD = 2.31E-10), and Gonadotropin Releasing Hormone Receptor (peGFR = 2.56E-15, pCKD = 5.45E-08, pESKD = 1.42E-08). All findings in MVP were replicated in CKDGen. The direction of effect was consistent across all findings, except for Gonadotropin Releasing Hormone Receptor which exhibited a positive effect in diabetic patients and a negative effect in non-diabetic patients.

Conclusion

Our findings highlight potential targets for therapeutic intervention in CKD. Pathway enrichment analyses are underway to explore underlying mechanisms. Further studies should confirm the causal relationship between druggable proteins and kidney outcomes.

Funding

  • Veterans Affairs Support