Li, Yong and Cheng, Yurong and Consolato, Francesco and Schiano, Guglielmo and Chong, Michael R. and Pietzner, Maik and Nguyen, Ngoc Quynh H. and Scherer, Nora and Biggs, Mary L. and Kleber, Marcus E. and Haug, Stefan and Goecmen, Burulca and Pigeyre, Marie and Sekula, Peggy and Steinbrenner, Inga and Schlosser, Pascal and Joseph, Christina B. and Brody, Jennifer A. and Grams, Morgan E. and Hayward, Caroline and Schultheiss, Ulla T. and Kraemer, Bernhard K. and Kronenberg, Florian and Peters, Annette and Seissler, Jochen and Steubl, Dominik and Then, Cornelia and Wuttke, Matthias and Maerz, Winfried and Eckardt, Kai-Uwe and Gieger, Christian and Boerwinkle, Eric and Psaty, Bruce M. and Coresh, Josef and Oefner, Peter J. and Pare, Guillaume and Langenberg, Claudia and Scherberich, Jurgen E. and Yu, Bing and Akilesh, Shreeram and Devuyst, Olivier and Rampoldi, Luca and Koettgen, Anna (2022) Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases. JCI INSIGHT, 7 (10): e157035. ISSN , 2379-3708
Full text not available from this repository. (Request a copy)Abstract
Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin???s complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TAMM-HORSFALL GLYCOPROTEIN; SERUM UROMODULIN; MOLECULAR-CLONING; DOMINANT MODIFIER; KIDNEY-FUNCTION; UMOD GENE; RISK; ASIALOGLYCOPROTEIN; BIOSYNTHESIS; METAANALYSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Sep 2023 10:17 |
| Last Modified: | 19 Sep 2023 10:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58826 |
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