Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0056414
Title: A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy
Authors: He B.
Österholm A.-M.
Ojala J.R.M.
Andersson A.-C.
Tryggvason K. 
Keywords: luciferase
animal cell
animal tissue
article
cell immortalization
clinical article
controlled study
diabetic nephropathy
embryo
enzyme activity
enzyme assay
gene
gene expression
gene expression regulation
human
human cell
immunofluorescence
mouse
NCK1 gene
nonhuman
pathogenesis
podocyte
protein expression
reporter gene
single nucleotide polymorphism
Western blotting
zebra fish
Adaptor Proteins, Signal Transducing
Animals
Animals, Genetically Modified
Chromosomes, Human, Pair 3
Diabetic Nephropathies
Gene Expression
Gene Expression Regulation
Gene Order
Genes, Reporter
Genetic Variation
Genotype
Humans
Kidney Glomerulus
Mice
Oncogene Proteins
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
Zebrafish
Issue Date: 2013
Citation: He B., Österholm A.-M., Ojala J.R.M., Andersson A.-C., Tryggvason K. (2013). A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy. PLoS ONE 8 (2) : e56414. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0056414
Rights: Attribution 4.0 International
Abstract: 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. © 2013 He et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161342
ISSN: 19326203
DOI: 10.1371/journal.pone.0056414
Rights: Attribution 4.0 International
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