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

Abstract

Background The genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy. Patients and methods We performed a genome-wide association study using 1000 Genomes-based imputation in type 1 diabetic patients comparing diabetic nephropathy cases with proteinuria with or without renal failure to controls with diabetes for more than 15 years and no evidence of renal disease. Results None of the SNPs tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p-value < 10−5) were then sought for first-stage analysis in US-GoKinD an independent population of 820 cases and 885 controls. Two SNPs, in strong linkage disequilibrium with each other, 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 [0.60 – 0.82]. However, this association was not observed in a second-stage with two additional diabetic nephropathy cohorts UK-ROI (p=0.15) and FINNDIANE (p = 0.44) totaling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analyzed rs1326934-C allele OR for diabetic nephropathy was 0.83 [0.72 – 0.96] (p = 0.009). Conclusion These data suggest that SORBS1 might be a gene involved in diabetic nephropathy.

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

“…Also, the various GWAS for DR and DKD have examined different case definitions including PDR, NPDR, DME, proteinuria, AER, and ESRD. In some studies, participants with NPDR and microproteinuria were classified as controls [43][44][45]87], whereas in other studies they were considered cases [46, 61,82,89].…”

“…In 2015, Germain et al performed a GWAS comparing T1D cases with proteinuria (with or without renal failure) with control patients who have had diabetes for more than 15 years and no evidence of renal disease [89]. No SNPs tested in a discovery cohort consisting of 683 cases and 779 controls reached genome-wide statistical significance.…”

Precision Medicine Approaches to Diabetic Kidney Disease: Tissue as an Issue

“…Furthermore, natural history studies (mostly in subjects with type1 DM) indicate that the degree of hyperglycemia correlates with DKD incidence. Based on these observations, investigators have tried to control glycemia almost to the degree of non-diabetic levels in the ACCORD, ADVANCE, and VA-DT clinical trials [24]. Surprisingly, these studies failed to show lower mortality and complication rates.…”

Lessons from CKD-Related Genetic Association Studies–Moving Forward

“…Interestingly, a transethnic meta-analysis revealed that the MYO16/IRS2 locus would be associated with susceptibility to both type 1 and 2 diabetic nephropathies (29), and a SCAF8 variant was consistently associated with type 2 diabetic nephropathy across populations of different ancestry (30) (see dark gray in Figure 2). In addition, GWAS carried out in European populations highlighted several associations with type 1 diabetes-associated ESRD (31,32), and other studies revealed candidates for both type 1-and type 2-associated ESRD (26,(33)(34)(35)(36)(37). However, a subsequent comprehensive, large, meta-GWAS effort was unable to identify clear loci consistently associated with diabetic nephropathy and many of the previous identified candidate signals were not validated (28).…”