Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

Diabetes. 2016 Mar;65(3):803-17. doi: 10.2337/db15-1313. Epub 2015 Dec 2.

Abstract

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Albuminuria / etiology
  • Albuminuria / genetics*
  • Animals
  • Cathepsin C / genetics
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / genetics*
  • Female
  • Gene Knockout Techniques
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Kidney / metabolism
  • Kidney Tubules / metabolism*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Rats
  • Receptors, Cell Surface / genetics
  • Sulfotransferases / genetics
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Receptors, Cell Surface
  • intrinsic factor-cobalamin receptor
  • Sulfotransferases
  • heparan sulfate 6-O-sulfotransferase
  • CTSC protein, human
  • Cathepsin C
  • RAB38 protein, human
  • Rab38 protein, rat
  • rab GTP-Binding Proteins

Grant support