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

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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

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Genome-Wide Association Study
Type 1 Diabetes Mellitus
Albumins
Albuminuria
Diabetic Nephropathies
Cellular Immunity
Natural Killer Cells
Antihypertensive Agents
Genes
Single Nucleotide Polymorphism
Population

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Sandholm, N., Forsblom, C., Mäkinen, V-P., McKnight, A. J., Osterholm, A-M., He, B., ... on behalf of The SUMMIT Consortium (2014). Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. Diabetologia, 57(6), 1143-1153. https://doi.org/10.1007/s00125-014-3202-3
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. / Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. In: Diabetologia. 2014 ; Vol. 57, No. 6. pp. 1143-1153.
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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.",
author = "Niina Sandholm and Carol Forsblom and Ville-Petteri M{\"a}kinen and McKnight, {Amy Jayne} and Anne-May Osterholm and Bing He and Valma Harjutsalo and Raija Lithovius and Daniel Gordin and Maija Parkkonen and Markku Saraheimo and Thorn, {Lena M} and Nina Tolonen and Johan Wad{\'e}n and Jaakko Tuomilehto and Maria Lajer and Emma Ahlqvist and Anna M{\"o}llsten and Marcovecchio, {M Loredana} and Jason Cooper and David Dunger and Paterson, {Andrew D} and Gianpaolo Zerbini and Leif Groop and Lise Tarnow and Maxwell, {Alexander P} and Karl Tryggvason and Per-Henrik Groop and {on behalf of The SUMMIT Consortium}",
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Sandholm, N, Forsblom, C, Mäkinen, V-P, McKnight, AJ, Osterholm, A-M, He, B, Harjutsalo, V, Lithovius, R, Gordin, D, Parkkonen, M, Saraheimo, M, Thorn, LM, Tolonen, N, Wadén, J, Tuomilehto, J, Lajer, M, Ahlqvist, E, Möllsten, A, Marcovecchio, ML, Cooper, J, Dunger, D, Paterson, AD, Zerbini, G, Groop, L, Tarnow, L, Maxwell, AP, Tryggvason, K, Groop, P-H & on behalf of The SUMMIT Consortium 2014, 'Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes', Diabetologia, vol. 57, no. 6, pp. 1143-1153. https://doi.org/10.1007/s00125-014-3202-3

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 journalArticle

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 -