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Abstract: SA-OR26

Genome-Wide Association Study (GWAS) in the Million Veteran Program of Diabetic Kidney Disease (DKD) Highlights Biology of the Glomerular Basement Membrane (GBM) and Tubular Transporter in DKD

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Fried, Linda F., University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
  • Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Sun, Yan, Emory University, Atlanta, Georgia, United States
  • Zhou, Jin, The University of Arizona College of Medicine Phoenix, Phoenix, Arizona, United States
  • Reaven, Peter, Phoenix VA Health Care System, Phoenix, Arizona, United States
  • Wilson, Peter W., Emory University, Atlanta, Georgia, United States
  • Phillips, Lawrence S., Emory University, Atlanta, Georgia, United States
Background

Diabetes is the most common cause of end-stage renal disease (ESRD) worldwide. Diabetic Kidney Disease (DKD) is defined by reduced kidney function and/or albuminuria. We here study the genetic determinants of DKD.

Methods

Our primary outcome was a composite of low estimated glomerular filtration rate (eGFR), or end-stage renal disease (ESRD). Cases had to meet criteria for diabetes for at least 5 years before the onset of DKD, while controls had to meet diabetes criteria for at least 7 years without DKD. Our secondary outcome was proteinuria/macroalbuminuria, no specific diabetes duration was required for the proteinuria cases. We conducted a large GWAS in 50,355 participants (21,273 cases) of European ancestry, and 18,144 (7,700 cases) of Non-Hispanic Blacks. Cases and controls were regressed onto additively coded genotypes imputed to a 1000 Genomes panel, with MAF>1%, adjusting for model 1: age, sex and 10 race/ethnicity-specific principal components and model 2: model 1 plus median HbA1c, BMI, and systolic blood pressure. Inverse-variance-weighted fixed-effects meta-analysis was conducted across race groups.
.

Results

Two loci reach genome-wide significance in the transethnic GWAS for low GFR or ESRD: rs113795872 (CUBN, p=9.8E-14), and rs71149134 (UMOD, p= 3.761E-32). We replicated the association with the one variant in COL4A3 reported as associated with DKD rs55703767 (p=0.02). Five loci that reach GWAS significant association with persistent gross proteinuria: CUBN (p=1.77 E-25), UMOD (4.5E-14), CCD158 (8.17E-10), SHROOM3 (6.69 E-09), and CEBPG (1.5 E-08).

Conclusion

Our study found 5 genome-wide significant associations with different manifestations of DKD. Some of the involved genes play a role as a component of the glomerular basement membrane or renal tubular function and may represent targets for therapy.

Funding

  • Veterans Affairs Support