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

Niina Sandholm, Carol Forsblom, Ville-Petteri Mäkinen, Amy Jayne McKnight, Anne-May Osterholm, Bing He, Valma Harjutsalo, Raija Lithovius, Daniel Gordin, Maija Parkkonen, Markku Saraheimo, Lena M Thorn, Nina Tolonen, Johan Wadén, Jaakko Tuomilehto, Maria Lajer, Emma Ahlqvist, Anna Möllsten, M Loredana Marcovecchio, Jason CooperDavid Dunger, Andrew D Paterson, Gianpaolo Zerbini, Leif Groop, Lise Tarnow, Alexander P Maxwell, Karl Tryggvason, Per-Henrik Groop, on behalf of The SUMMIT Consortium

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 × 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.
Original languageEnglish
Pages (from-to)1143-1153
Number of pages11
JournalDiabetologia
Volume57
Issue number6
Early online date05 Mar 2014
DOIs
Publication statusPublished - Jun 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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