SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes

Marine Germain, Marcus G. Pezzolesi, Niina Sandholm, Amy J. McKnight, Katalin Susztak, Maria Lajer, Carol Forsblom, Michel Marre, Hans-Henrik Parving, Peter Rossing, Iiro Toppila, Jan Skupien, Ronan Roussel, Yi-An Ko, Nora Ledo, Lasse Folkersen, Mete Civelek, Alexander P. Maxwell, David-Alexandre Tregouet, Per-Henrik GroopLise Tarnow, Samy Hadjadj

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis

The genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.

Methods

We performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease.

Results

None of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10−5) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10−4) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95% CI 0.72, 0.96; p = 0.009).

Conclusions/interpretation

These data suggest that SORBS1 might be a gene involved in diabetic nephropathy.

Original languageEnglish
Pages (from-to)543-548
JournalDiabetologia
Volume58
Issue number3
Early online date06 Dec 2014
DOIs
Publication statusPublished - Mar 2015

Fingerprint

Genome-Wide Association Study
Diabetic Nephropathies
Type 1 Diabetes Mellitus
Genes
Kidney
Ireland
Single Nucleotide Polymorphism
Alleles
Genome
Linkage Disequilibrium
Proteinuria
Renal Insufficiency

Cite this

Germain, Marine ; Pezzolesi, Marcus G. ; Sandholm, Niina ; McKnight, Amy J. ; Susztak, Katalin ; Lajer, Maria ; Forsblom, Carol ; Marre, Michel ; Parving, Hans-Henrik ; Rossing, Peter ; Toppila, Iiro ; Skupien, Jan ; Roussel, Ronan ; Ko, Yi-An ; Ledo, Nora ; Folkersen, Lasse ; Civelek, Mete ; Maxwell, Alexander P. ; Tregouet, David-Alexandre ; Groop, Per-Henrik ; Tarnow, Lise ; Hadjadj, Samy. / SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes. In: Diabetologia. 2015 ; Vol. 58, No. 3. pp. 543-548.
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abstract = "Aims/hypothesisThe genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.MethodsWe performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease.ResultsNone of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10−5) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10−4) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95{\%} CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95{\%} CI 0.72, 0.96; p = 0.009).Conclusions/interpretationThese data suggest that SORBS1 might be a gene involved in diabetic nephropathy.",
author = "Marine Germain and Pezzolesi, {Marcus G.} and Niina Sandholm and McKnight, {Amy J.} and Katalin Susztak and Maria Lajer and Carol Forsblom and Michel Marre and Hans-Henrik Parving and Peter Rossing and Iiro Toppila and Jan Skupien and Ronan Roussel and Yi-An Ko and Nora Ledo and Lasse Folkersen and Mete Civelek and Maxwell, {Alexander P.} and David-Alexandre Tregouet and Per-Henrik Groop and Lise Tarnow and Samy Hadjadj",
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Germain, M, Pezzolesi, MG, Sandholm, N, McKnight, AJ, Susztak, K, Lajer, M, Forsblom, C, Marre, M, Parving, H-H, Rossing, P, Toppila, I, Skupien, J, Roussel, R, Ko, Y-A, Ledo, N, Folkersen, L, Civelek, M, Maxwell, AP, Tregouet, D-A, Groop, P-H, Tarnow, L & Hadjadj, S 2015, 'SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes', Diabetologia, vol. 58, no. 3, pp. 543-548. https://doi.org/10.1007/s00125-014-3459-6

SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes. / Germain, Marine; Pezzolesi, Marcus G.; Sandholm, Niina; McKnight, Amy J.; Susztak, Katalin; Lajer, Maria; Forsblom, Carol; Marre, Michel; Parving, Hans-Henrik; Rossing, Peter; Toppila, Iiro; Skupien, Jan; Roussel, Ronan; Ko, Yi-An; Ledo, Nora; Folkersen, Lasse; Civelek, Mete; Maxwell, Alexander P.; Tregouet, David-Alexandre; Groop, Per-Henrik; Tarnow, Lise; Hadjadj, Samy.

In: Diabetologia, Vol. 58, No. 3, 03.2015, p. 543-548.

Research output: Contribution to journalArticle

TY - JOUR

T1 - SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes

AU - Germain, Marine

AU - Pezzolesi, Marcus G.

AU - Sandholm, Niina

AU - McKnight, Amy J.

AU - Susztak, Katalin

AU - Lajer, Maria

AU - Forsblom, Carol

AU - Marre, Michel

AU - Parving, Hans-Henrik

AU - Rossing, Peter

AU - Toppila, Iiro

AU - Skupien, Jan

AU - Roussel, Ronan

AU - Ko, Yi-An

AU - Ledo, Nora

AU - Folkersen, Lasse

AU - Civelek, Mete

AU - Maxwell, Alexander P.

AU - Tregouet, David-Alexandre

AU - Groop, Per-Henrik

AU - Tarnow, Lise

AU - Hadjadj, Samy

PY - 2015/3

Y1 - 2015/3

N2 - Aims/hypothesisThe genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.MethodsWe performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease.ResultsNone of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10−5) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10−4) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95% CI 0.72, 0.96; p = 0.009).Conclusions/interpretationThese data suggest that SORBS1 might be a gene involved in diabetic nephropathy.

AB - Aims/hypothesisThe genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.MethodsWe performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease.ResultsNone of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10−5) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10−4) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95% CI 0.72, 0.96; p = 0.009).Conclusions/interpretationThese data suggest that SORBS1 might be a gene involved in diabetic nephropathy.

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DO - 10.1007/s00125-014-3459-6

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JO - Diabetologia

JF - Diabetologia

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