Document Detail


Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels.
MedLine Citation:
PMID:  23344472     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia with decreased renal excretion of UMOD and uric acid, suggesting a role for UMOD in the regulation of plasma uric acid. To determine this, we screened common variants across the UMOD locus in one community-based Chinese population of 1000 individuals and the other population from 642 American twins and siblings of European and Hispanic ancestry. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK-293 cells and mIMCD3 cells. In the primary Chinese population, we found that carriers of the GCC haplotype had higher plasma uric acid, and three promoter variants were associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in the independent American cohort. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. Thus, UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, leading to altered plasma uric acid levels.
Authors:
Jia Han; Ying Liu; Fangwen Rao; Caroline M Nievergelt; Daniel T O'Connor; Xingyu Wang; Lisheng Liu; Dingfang Bu; Yu Liang; Fang Wang; Luxia Zhang; Hong Zhang; Yuqing Chen; Haiyan Wang
Publication Detail:
Type:  Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't; Twin Study     Date:  2013-01-23
Journal Detail:
Title:  Kidney international     Volume:  83     ISSN:  1523-1755     ISO Abbreviation:  Kidney Int.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-29     Completed Date:  2013-09-24     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  733-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Asian Continental Ancestry Group / genetics
Biological Markers / blood,  urine
California
China
Creatinine / urine
European Continental Ancestry Group / genetics
Female
Gene Expression Regulation
Genes, Reporter
HEK293 Cells
Haplotypes
Hispanic Americans / genetics
Humans
Linear Models
Male
Middle Aged
Mutagenesis, Site-Directed
Phenotype
Polymorphism, Single Nucleotide*
Promoter Regions, Genetic
Sodium / urine
Transcription, Genetic*
Transfection
Uric Acid / blood*,  urine
Uromodulin / genetics*
Grant Support
ID/Acronym/Agency:
KL2 TR000099/TR/NCATS NIH HHS; P01 HL058120/HL/NHLBI NIH HHS; P60 MD000220/MD/NIMHD NIH HHS; R01 DK094894/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/UMOD protein, human; 0/Uromodulin; 268B43MJ25/Uric Acid; 9NEZ333N27/Sodium; AYI8EX34EU/Creatinine
Comments/Corrections
Comment In:
Kidney Int. 2013 Aug;84(2):411-3   [PMID:  23903423 ]
Kidney Int. 2013 Aug;84(2):410-1   [PMID:  23903422 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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