Abstract
The 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.
| Original language | English |
|---|---|
| Pages (from-to) | 543-548 |
| Journal | Diabetologia |
| Volume | 58 |
| Issue number | 3 |
| Early online date | 06 Dec 2014 |
| DOIs | |
| Publication status | Published - Mar 2015 |
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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 journal › Article
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.
U2 - 10.1007/s00125-014-3459-6
DO - 10.1007/s00125-014-3459-6
M3 - Article
C2 - 25476525
VL - 58
SP - 543
EP - 548
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 3
ER -