title: Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.
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.
authors.affiliation: National 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;
authors.forename: Matthias
authors.initials: M
authors.lastname: Olden
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland;
authors.forename: Tanguy
authors.initials: T
authors.lastname: Corre
authors.affiliation: Institute of Genetics and Molecular Medicine, Western General Hospital, and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; Institute of Molecular Genetics, National Research Council, Pavia, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.affiliation: Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy;
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulivi
authors.affiliation: Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts;
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland;
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy;
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cocca
authors.affiliation: Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy;
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gandin
authors.affiliation: Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy;
authors.forename: Giorgia
authors.initials: G
authors.lastname: Girotto
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, and.
authors.forename: Bob
authors.initials: B
authors.lastname: Glaudemans
authors.affiliation: Institute of Genetics and Molecular Medicine, Western General Hospital, and.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland;
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Department of Public Health, Faculty of Medicine, University of Split, Croatia;
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
authors.affiliation: Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany;
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sala
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy;
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Department of Internal Medicine, Lausanne University Hospital, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Institute for Maternal and Child Health, Burlo Garofolo Pediatric Institute Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy;
authors.forename: Dragana
authors.initials: D
authors.lastname: Vuckovic
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium;
authors.forename: Sonia
authors.initials: S
authors.lastname: Youhanna
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium;
authors.forename: Julien
authors.initials: J
authors.lastname: Weber
authors.affiliation: Institute of Genetics and Molecular Medicine, Western General Hospital, and.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Department 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.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland; and.
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium; olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D003404:Creatinine / Q000378:metabolism; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058949:Uromodulin / Q000235:genetics / Q000652:urine*; D044465:White People / Q000235:genetics*
chemical_list: C548612:UMOD protein, human; D058949:Uromodulin; D003404:Creatinine