Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans

Hum Genet. 2016 Nov;135(11):1251-1262. doi: 10.1007/s00439-016-1714-2. Epub 2016 Jul 26.

Abstract

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.

Publication types

  • Meta-Analysis

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Cytoskeletal Proteins / genetics
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / pathology
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Glomerular Basement Membrane / metabolism
  • Glomerular Basement Membrane / ultrastructure
  • Haplotypes
  • Humans
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / genetics*
  • Kidney Failure, Chronic / pathology
  • Kidney Tubules, Distal / metabolism
  • Kidney Tubules, Distal / ultrastructure
  • Male
  • Matrix Metalloproteinase 2 / genetics
  • Mesangial Cells / metabolism
  • Mesangial Cells / ultrastructure
  • Middle Aged
  • Podocytes / metabolism
  • Podocytes / ultrastructure
  • Polymorphism, Single Nucleotide

Substances

  • Adaptor Proteins, Signal Transducing
  • CD2-associated protein
  • Cytoskeletal Proteins
  • MMP2 protein, human
  • Matrix Metalloproteinase 2