Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels.
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.
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Jia
J
Han
Ying
Y
Liu
Fangwen
F
Rao
Caroline M
CM
Nievergelt
Daniel T
DT
O'Connor
Xingyu
X
Wang
Lisheng
L
Liu
Dingfang
D
Bu
Yu
Y
Liang
Fang
F
Wang
Luxia
L
Zhang
Hong
H
Zhang
Yuqing
Y
Chen
Haiyan
H
Wang
D000704:Analysis of Variance; D044466:Asian People / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002140:California; D002681:China; D003404:Creatinine / Q000652:urine; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012964:Sodium / Q000652:urine; D014158:Transcription, Genetic; D014162:Transfection; D014527:Uric Acid / Q000097:blood* / Q000652:urine; D058949:Uromodulin / Q000235:genetics*; D044465:White People / Q000235:genetics
D015415:Biomarkers; C548612:UMOD protein, human; D058949:Uromodulin; D014527:Uric Acid; D012964:Sodium; D003404:Creatinine