PUBLICATION
A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease
- Authors
- Sun, C.Y., Wu, M.S., Lee, C.C., Chen, S.H., Lo, K.C., Chen, Y.H.
- ID
- ZDB-PUB-180530-3
- Date
- 2018
- Source
- Scientific Reports 8: 8085 (Journal)
- Registered Authors
- Chen, Yau-Hung
- Keywords
- none
- MeSH Terms
-
- 5' Flanking Region/genetics*
- Aged
- Case-Control Studies
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Organic Anion Transport Protein 1/genetics*
- Polymorphism, Single Nucleotide*
- Promoter Regions, Genetic/genetics*
- Renal Insufficiency, Chronic/epidemiology
- Renal Insufficiency, Chronic/genetics*
- Risk Factors
- PubMed
- 29795395 Full text @ Sci. Rep.
Citation
Sun, C.Y., Wu, M.S., Lee, C.C., Chen, S.H., Lo, K.C., Chen, Y.H. (2018) A novel SNP in the 5' regulatory region of organic anion transporter 1 is associated with chronic kidney disease. Scientific Reports. 8:8085.
Abstract
We aimed to analyze the associations of single nucleotide polymorphisms (SNP) in the 5' regulatory region of the human organic anion transporter 1 (OAT1) gene with chronic kidney disease (CKD). A case-control study including age- and sex-matched groups of normal subjects and patients with CKD (nâ=â162 each) was designed. Direct sequencing of the 5' regulatory region (+88 to -1196 region) showed that patients with CKD had a higher frequency of the -475 SNP (Tâ>âT/G) than normal subjects (14/162 vs. 2/162). The luciferase activity assay results indicated that the -475G SNP had a higher promoter efficiency than the -475T SNP. Chromatin immunoprecipitation (ChIP) and LC/MS/MS analyses showed that the -475G SNP up-regulated 26 proteins and down-regulated 74 proteins. The Southwestern blot assay results revealed that the -475G SNP decreased the binding of Hepatoma-derived growth factor (HDGF), a transcription repressor, compared to the -475T SNP. Overexpression of HDGF significantly down-regulated OAT1 in renal tubular cells. Moreover, a zebrafish animal model showed that HDGF-knockdown zebrafish embryos had higher rates of kidney malformation than wild-type controls [18/78 (23.1%) vs. 1/30 (3.3%)]. In conclusion, our results suggest that an OAT1 SNP might be clinically associated with CKD. Renal tubular cells with the -475 SNP had increased OAT1 expression, which resulted in increased transportation of organic anion toxins into cells. Cellular accumulation of organic anion toxins caused cytotoxicity and resulted in CKD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping