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 Groop; Lise Tarnow; Samy Hadjadj

doi: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

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

Institut for Klinisk Medicin

24 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	58
Udgave nummer	3
Sider (fra-til)	543-8
Antal sider	6
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-014-3459-6
Status	Udgivet - mar. 2015

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Germain, M., Pezzolesi, M. G., Sandholm, N., McKnight, A. J., 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, A. P., Tregouet, D-A., ... 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, 58(3), 543-8. https://doi.org/10.1007/s00125-014-3459-6

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, bind 58, nr. 3, s. 543-8. https://doi.org/10.1007/s00125-014-3459-6

@article{404e2633da7d4e27aa6ec677ef561b75,

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

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.",

keywords = "Diabetes Mellitus, Type 1, Diabetic Nephropathies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Microfilament Proteins, Middle Aged, Polymorphism, Single Nucleotide",

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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doi = "10.1007/s00125-014-3459-6",

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T1 - SORBS1 gene, a new candidate for diabetic nephropathy

T2 - 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/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.

AB - 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.

KW - Diabetes Mellitus, Type 1

KW - Diabetic Nephropathies

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Microfilament Proteins

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

U2 - 10.1007/s00125-014-3459-6

DO - 10.1007/s00125-014-3459-6

M3 - Letter

C2 - 25476525

SN - 0012-186X

VL - 58

SP - 543

EP - 548

JO - Diabetologia

JF - Diabetologia

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ER -

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

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