SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes
Publikation: Bidrag til tidsskrift › Letter › Forskning › fagfællebedømt
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 & 2 andre
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.
|Status||Udgivet - mar. 2015|