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Abstract: TH-PO859

Genome-Wide Association Study of Urinary and Plasma KIM-1 Levels in Type 1 Diabetic Subjects with Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Pezzolesi, Marcus G., University of Utah, Salt Lake City, Utah, United States
  • Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Smiles, Adam, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Simeone, Christopher, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Fierro, Julio Cesar, University of Utah, Salt Lake City, Utah, United States
  • Krolewski, Bozena, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Rich, Stephen, University of Virginia, Charlottesville, Virginia, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

Kidney injury molecule 1 (KIM-1) is a transmembrane protein primarily expressed at the apical membrane of proximal tubular cells following kidney damage. Urinary and plasma levels of this biomarker are increased in patients with non-diabetic chronic kidney disease and diabetic kidney disease. Here, we performed a genome-wide association study (GWAS) to investigate whether genetic factors influence urinary and plasma KIM-1 levels in type 1 diabetes.

Methods

KIM-1 levels were measured in 688 baseline urine specimens and 826 plasma specimens from participants with type 1 diabetes enrolled in the Joslin Kidney Study. Genotyping was performed using Illumina’s HumanCoreExome BeadArray. Imputation of additional variants across the KIM-1 locus was performed using IMPUTE2 and 1000 Genomes Phase 3 data. Association analyses between KIM-1 levels and single nucleotide polymorphism (SNP) data were calculated using linear regression implemented in Plink.

Results

The strongest GWAS SNP associated with urinary KIM-1 levels was a missense variant (rs12522248; Thr207Ala; P=6.3x10-6) located in exon 3 of the KIM1 gene. The most strongly associated GWAS SNP with plasma KIM-1 levels was rs2436424 (P=5.0x10-6), located 230kb downstream of KIM1. Using imputed SNPs to fine-map this locus, we identified 45 SNPs with P<1.0x10-5, including 2 variants approximately 50kb downstream of KIM1 with P<1x10-7.

Conclusion

Using a GWAS and imputation analysis of urinary and plasma KIM-1 levels, we identified strong associations in the KIM1 gene that suggests that genetic variants at this locus impact KIM-1 levels in response to kidney injury. Further investigation is needed to fully understand the role of genetic variation on KIM-1 levels and how these potentially impact the utility of this biomarker in patients with or at risk of diabetic kidney disease.

Funding

  • Private Foundation Support