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J Am Soc Nephrol. 2014 Aug;25(8):1869-82. doi: 10.1681/ASN.2013070781. Epub 2014 Feb 27.

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Author information

  • 1National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany;
  • 2Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland;
  • 3Institute of Genetics and Molecular Medicine, Western General Hospital, and.
  • 4Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; Institute of Molecular Genetics, National Research Council, Pavia, Italy;
  • 5Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy;
  • 6Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy;
  • 7Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy;
  • 8National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts;
  • 9Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy;
  • 10Institute of Physiology, Zurich Center for Integrative Human Physiology, and.
  • 11Institute of Anatomy, University of Zurich, Zurich, Switzerland;
  • 12Department of Public Health, Faculty of Medicine, University of Split, Croatia;
  • 13Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany;
  • 14Department of Internal Medicine, Lausanne University Hospital, and.
  • 15Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium;
  • 16Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland; and.
  • 17Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland; and.
  • 18National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 19Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium; olivier.devuyst@uzh.ch.

Abstract

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

Copyright © 2014 by the American Society of Nephrology.

PMID:
24578125
[PubMed - indexed for MEDLINE]
PMCID:
PMC4116060
[Available on 2015-08-01]
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