Abstract: FR-OR039

Novel Loci for Renal Decline in Type 1 Diabetes (T1D)

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Pezzolesi, Marcus G., University of Utah, Salt Lake City, Utah, United States
  • Chen, Wei-Min, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Forsblom, Carol, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
  • Mychaleckyj, Josyf, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Marre, Michel, INSERM, Poitiers, France
  • Rich, Stephen, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Galecki, Andrzej, University of Michigan, Ann Arbor, Michigan, United States
  • Hadjadj, Samy, INSERM, Poitiers, France
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Groop, Per-Henrik, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Skupien, Jan, Joslin Diabetes Center, Boston, United States
  • Wu, Chunyi, University of Michigan, Ann Arbor, Michigan, United States
  • Smiles, Adam, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Ahluwalia, Tarunveer Singh, Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Sandholm, Niina, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
  • Valo, Erkka A., Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
  • György, Beáta, INSERM, Poitiers, France
  • Onengut-Gumuscu, Suna, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Progressive renal decline is the predominant clinical feature of diabetic kidney disease (DKD) that leads to end-stage renal disease. Although genetic factors are known to contribute to DKD’s susceptibility, despite intense effort, the identification of variants that underlie its risk has proven challenging. To advance this area of research, as part of the JDRF-sponsored Diabetic Nephropathy Collaborative Research Initiative, we recently performed the first genome-wide association study (GWAS) aimed at identifying variants associated with progressive renal decline in T1D.

Methods

We performed a linear mixed-effects model (LMM) meta-GWAS using serial measures of estimated glomerular filtration rate (eGFR) to estimate the effects of genetic variants on eGFR slope in 1,614 T1D patients with proteinuria assembled from 4 cohorts of European ancestry (Boston, Finland, Denmark and France). In total, more than 38,000 longitudinal eGFR measures collected over 5-20 years of follow-up were used to establish eGFR slopes in these patients.

Results

Our LMM meta-GWAS identified several novel loci that were strongly associated with eGFR decline. Our top finding was a variant in LRP1B that approached genome-wide significance (P=7.3x10-8). In total, 37 variants across 20 distinct loci achieved P<1x10-4, including 6 variants with P<1x10-6 in genes not previously associated with DKD. In addition to novel loci for progressive renal function decline, our LMM meta-GWAS replicated an association at FRMD3, a gene that we initially identified as part of our GWAS in the GoKinD collection.

Conclusion

Using a LMM meta-GWAS approach and longitudinal measures of renal function, we discovered several novel loci that contribute to progressive renal decline in patients with T1D and, thereby, further our understanding of the biology underlying DKD.

Funding

  • Private Foundation Support