Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1143-1153 |
| Number of pages | 11 |
| Journal | Diabetologia |
| Volume | 57 |
| Issue number | 6 |
| Early online date | 05 Mar 2014 |
| DOIs | |
| Publication status | Published - Jun 2014 |
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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. / Sandholm, Niina; Forsblom, Carol; Mäkinen, Ville-Petteri; McKnight, Amy Jayne; Osterholm, Anne-May; He, Bing; Harjutsalo, Valma; Lithovius, Raija; Gordin, Daniel; Parkkonen, Maija; Saraheimo, Markku; Thorn, Lena M; Tolonen, Nina; Wadén, Johan; Tuomilehto, Jaakko; Lajer, Maria; Ahlqvist, Emma; Möllsten, Anna; Marcovecchio, M Loredana; Cooper, Jason; Dunger, David; Paterson, Andrew D; Zerbini, Gianpaolo; Groop, Leif; Tarnow, Lise; Maxwell, Alexander P; Tryggvason, Karl; Groop, Per-Henrik; on behalf of The SUMMIT Consortium.
In: Diabetologia, Vol. 57, No. 6, 06.2014, p. 1143-1153.Research output: Contribution to journal › Article
TY - JOUR
T1 - Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes
AU - Sandholm, Niina
AU - Forsblom, Carol
AU - Mäkinen, Ville-Petteri
AU - McKnight, Amy Jayne
AU - Osterholm, Anne-May
AU - He, Bing
AU - Harjutsalo, Valma
AU - Lithovius, Raija
AU - Gordin, Daniel
AU - Parkkonen, Maija
AU - Saraheimo, Markku
AU - Thorn, Lena M
AU - Tolonen, Nina
AU - Wadén, Johan
AU - Tuomilehto, Jaakko
AU - Lajer, Maria
AU - Ahlqvist, Emma
AU - Möllsten, Anna
AU - Marcovecchio, M Loredana
AU - Cooper, Jason
AU - Dunger, David
AU - Paterson, Andrew D
AU - Zerbini, Gianpaolo
AU - Groop, Leif
AU - Tarnow, Lise
AU - Maxwell, Alexander P
AU - Tryggvason, Karl
AU - Groop, Per-Henrik
AU - on behalf of The SUMMIT Consortium
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
U2 - 10.1007/s00125-014-3202-3
DO - 10.1007/s00125-014-3202-3
M3 - Article
C2 - 24595857
VL - 57
SP - 1143
EP - 1153
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 6
ER -