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

22 Citations (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.

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

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