title: Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.
abstract: OBJECTIVE
  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 × 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
  This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Anne-May
authors.initials: AM
authors.lastname: Osterholm
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.forename: Raija
authors.initials: R
authors.lastname: Lithovius
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.forename: Maija
authors.initials: M
authors.lastname: Parkkonen
authors.forename: Markku
authors.initials: M
authors.lastname: Saraheimo
authors.forename: Lena M
authors.initials: LM
authors.lastname: Thorn
authors.forename: Nina
authors.initials: N
authors.lastname: Tolonen
authors.forename: Johan
authors.initials: J
authors.lastname: Wadén
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: Anna
authors.initials: A
authors.lastname: Möllsten
authors.forename: M Loredana
authors.initials: ML
authors.lastname: Marcovecchio
authors.forename: Jason
authors.initials: J
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Dunger
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000652:urine*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics