Common Variants in UMOD Associate with Urinary Uromodulin Levels: A Meta-Analysis

Matthias Olden, Tanguy Corre, Caroline Hayward, Daniela Toniolo, Sheila Ulivi, Paolo Gasparini, Giorgio Pistis, Shih-Jen Hwang, Sven Bergmann, Harry Campbell, Massimiliano Cocca, Ilaria Gandin, Giorgia Girotto, Bob Glaudemans, Nicholas D Hastie, Johannes Loffing, Ozren Polasek, Luca Rampoldi, Igor Rudan, Cinzia SalaMichela Traglia, Peter Vollenweider, Dragana Vuckovic, Sonia Youhanna, Julien Weber, Alan F Wright, Zoltán Kutalik, Murielle Bochud, Caroline S Fox, Olivier Devuyst

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
JournalJournal of the American Society of Nephrology
Publication statusPublished - 27 Feb 2014


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