Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels

Han, Jia; Liu, Ying; Rao, Fangwen; Nievergelt, Caroline M; O'Connor, Daniel T; Wang, Xingyu; Liu, Lisheng; Bu, Dingfang; Liang, Yu; Wang, Fang; Zhang, Luxia; Zhang, Hong; Chen, Yuqing; Wang, Haiyan
April 2013
Kidney International;Apr2013, Vol. 83 Issue 4, p733
Academic Journal
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.


Related Articles

  • Population Haplotypes of Exon ORF15 of the Retinitis Pigmentosa GTPase Regulator Gene in Germany. Karra, Daniela; Jacobi, Felix K.; Broghammer, Martina; Blin, Nikolaus; Pusch, Carsten M. // Molecular Diagnosis & Therapy;Mar2006, Vol. 10 Issue 2, p115 

    Background: Mutations in exon ORF15 of the retinitis pigmentosa GTPase regulator gene (RPGR) within chromosomal region Xp21.1 are a significant cause of a number of retinal disorders. The high mutation rate is ascribed to the highly repetitive, purine-rich tracts within the exon ORF15 sequence....

  • Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation. Moleirinho, Ana; Seixas, Susana; Lopes, Alexandra M.; Bento, Celeste; Prata, Maria J.; Amorim, António // Genome Biology & Evolution;Mar2013, Vol. 5 Issue 3, p559 

    Human hemoglobins, the oxygen carriers in the blood, are composed by two α-like and two β-like globin monomers. The β-globin gene cluster located at 11p15.5 comprises one pseudogene and five genes whose expression undergoes two critical switches: the embryonic-to-fetal and...

  • The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity. Petrovski, Slavé; Gussow, Ayal B.; Wang, Quanli; Halvorsen, Matt; Han, Yujun; Weir, William H.; Allen, Andrew S.; Goldstein, David B. // PLoS Genetics;9/2/2015, Vol. 11 Issue 9, p1 

    Noncoding sequence contains pathogenic mutations. Yet, compared with mutations in protein-coding sequence, pathogenic regulatory mutations are notoriously difficult to recognize. Most fundamentally, we are not yet adept at recognizing the sequence stretches in the human genome that are most...

  • Interpreting noncoding genetic variation in complex traits and human disease. Ward, Lucas D; Kellis, Manolis // Nature Biotechnology;Nov2012, Vol. 30 Issue 11, p1095 

    Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has focused primarily on protein-coding variants, owing to the difficulty of interpreting noncoding mutations. This picture has changed with advances in the systematic annotation...

  • Between proteins and phenotypes: annotation and interpretation of mutations. Baker, Christopher J. O.; Rebholz-Schuhmann, Dietrich // BMC Bioinformatics;2009 Supplement 8, Vol. 10, p1 

    The article discusses various reports published within the issue, including one on mutation related information technology (IT) solutions, and another on reporting on genetic variability.

  • The effect of common uromodulin variants on urinary protein level and gene transcription. Rampoldi, Luca; Köttgen, Anna; Devuyst, Olivier // Kidney International;Aug2013, Vol. 84 Issue 2, p410 

    A letter to the editor is presented in response to the article "Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels," by J. Han and colleagues in the 2013 issue.

  • Genetic Variation at Nine Short Tandem Repeat Loci Among Islanders of the Eastern Adriatic Coast of Croatia. Klarić, Irena Martinović; Peričić, Marijana; Lauc, Lovorka Barać; Janićijević, Branka; Kubat, Milovan; Pavičić, Dino; Rudan, Igor; Ning Wang; Lin Jin; Chakraborty, Ranajit; Deka, Ranjan; Rudan, Pavao // Human Biology;Aug2005, Vol. 77 Issue 4, p471 

    We have analyzed the extent of genetic variation at nine autosomal short tandem repeat loci (D3S1358, VWA, FGA, Th01, TPOX, CSF1PO, D5S818, D13S317, D7S820) among six populations from Croatia: five distributed in the islands of the eastern Adriatic coast and one from the mainland. The purpose is...

  • A common variant of HMGA2 is associated with adult and childhood height in the general population. Weedon, Michael N.; Lettre, Guillaume; Freathy, Rachel M.; Lindgren, Cecilia M.; Voight, Benjamin F.; Perry, John R. B.; Elliott, Katherine S.; Hackett, Rachel; Guiducci, Candace; Shields, Beverley; Zeggini, Eleftheria; Lango, Hana; Lyssenko, Valeriya; Timpson, Nicholas J.; Burtt, Noel P.; Rayner, Nigel W.; Saxena, Richa; Ardlie, Kristin; Tobias, Jonathan H.; Ness, Andrew R. // Nature Genetics;Oct2007, Vol. 39 Issue 10, p1245 

    Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 ×...

  • Mutational effects and the evolution of new protein functions. Soskine, Misha; Tawfik, Dan S. // Nature Reviews Genetics;Aug2010, Vol. 11 Issue 8, p572 

    The divergence of new genes and proteins occurs through mutations that modulate protein function. However, mutations are pleiotropic and can have different effects on organismal fitness depending on the environment, as well as opposite effects on protein function and dosage. We review the...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics