| Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. | |
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MedLine Citation:
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PMID: 23344472 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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.Kidney International advance online publication, 23 January 2013; doi:10.1038/ki.2012.449. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2013-1-23 |
Journal Detail:
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Title: Kidney international Volume: - ISSN: 1523-1755 ISO Abbreviation: Kidney Int. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0323470 Medline TA: Kidney Int Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China. |
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