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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

In English

Författare

  • Niina Sandholm
  • Carol Forsblom
  • Ville-Petteri Makinen
  • Amy Jayne McKnight
  • Anne-May Osterholm
  • Bing He
  • Valma Harjutsalo
  • Raija Lithovius
  • Daniel Gordin
  • Maija Parkkonen
  • Markku Saraheimo
  • Lena M. Thorn
  • Nina Tolonen
  • Johan Waden
  • Jaakko Tuomilehto
  • Maria Lajer
  • Emma Ahlqvist
  • Anna Mollsten
  • M. Loredana Marcovecchio
  • Jason Cooper
  • David Dunger
  • Andrew D. Paterson
  • Gianpaolo Zerbini
  • Leif Groop
  • Lise Tarnow
  • Alexander P. Maxwell
  • Karl Tryggvason
  • Per-Henrik Groop
Visa allt

Summary, in English

Aims/hypothesis An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. Methods The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value < 10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. Results The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 x 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. Conclusions/interpretation This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Publiceringsår

2014

Språk

Engelska

Sidor

1143-1153

Publikation/Tidskrift/Serie

Diabetologia

Volym

57

Issue

6

Dokumenttyp

Artikel i tidskrift

Förlag

Springer

Ämne

  • Endocrinology and Diabetes

Nyckelord

  • Albumin excretion rate
  • Albuminuria
  • Diabetic nephropathy
  • Genetics
  • GLRA3
  • GWAS
  • Heritability
  • Type 1 diabetes

Status

Published

Forskningsgrupp

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Övrigt

  • ISSN: 1432-0428