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

Aims/hypothesis<p class="a-plus-plus">The genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.</p>Methods<p class="a-plus-plus">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.</p>Results<p class="a-plus-plus">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 (<em class="a-plus-plus">p</em> < 10<sup class="a-plus-plus">−5</sup>) 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 <em class="a-plus-plus">SORBS1</em> gene were consistently and significantly (<em class="a-plus-plus">p</em> < 10<sup class="a-plus-plus">−4</sup>) 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; <em class="a-plus-plus">p</em> = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; <em class="a-plus-plus">p</em> = 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; <em class="a-plus-plus">p</em> = 0.009).</p>Conclusions/interpretation<p class="a-plus-plus">These data suggest that <em class="a-plus-plus">SORBS1</em> might be a gene involved in diabetic nephropathy.</p>