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We have previously reported genetic association of a single nucleotide polymorphism (SNP), rs1866813, at 3q locus with increased risk of diabetic nephropathy (DN). The SNP is located approximately 70 kb downstream of a cluster of four genes. This raises a question how the remote noncoding polymorphism affects the risk of DN. In this study, we tested a long-range regulatory potential of this variant by a series of experiments. In a luciferase assay, two alleles of the SNP showed differential effects on the luciferase activity in transfected cells  in vitro . Using transgenic zebrafish, we further demonstrated  in vivo  that two alleles of the SNP differentially regulated GFP expression in zebrafish podocytes. Immunofluorescence staining and Western blotting verified that only  Nck1  of the four nearby genes was predominantly expressed in mouse glomeruli as well as in podocytes. Furthermore, genotypes of the SNP rs1866813 were correlated with  NCK1  expression in immortalized lymphocytes from diabetic patients. The risk allele was associated with increased  NCK1  expression compared to the non-risk allele, consistent with the results of the reporter-based studies. Interestingly, differential expression of glomerular  Nck1  between mouse strains carrying the nephropathy-prone 129/Sv allele and nephropathy-resistant C57BL/6 allele was also observed. Our results show that the DN-associated SNP rs1866813 is a remote  cis -acting variant differentially regulating glomerular  NCK1  expression. This finding implicates an important role for glomerular NCK1 in DN pathogenesis under hyperglycemia.

A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy