| Title: |
Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases |
| Authors: |
Li, Y; Cheng, Y; Consolato, F; Schiano, G; Chong, MR; Pietzner, M; Nguyen, NQH; Scherer, N; Biggs, ML; Kleber, ME; Haug, S; Goecmen, B; Pigeyre, M; Sekula, P; Steinbrenner, I; Schlosser, P; Joseph, CB; Brody, JA; Grams, ME; Hayward, C; Schultheiss, UT; Kraemer, BK; Kronenberg, F; Peters, A; Seissler, J; Steubl, D; Then, C; Wuttke, M; Maerz, W; Eckardt, K-U; Gieger, C; Boerwinkle, E; Psaty, BM; Coresh, J; Oefner, PJ; Pare, G; Langenberg, C; Scherberich, JE; Yu, B; Akilesh, S; Devuyst, O; Rampoldi, L; Koettgen, A |
| Publisher Information: |
American Society for Clinical Investigation (ASCI) |
| Publication Year: |
2022 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
JCI INSIGHT; JCI Insight. 2022;7(10):e157035. https://doi.org/10.1172/jci. insight.157035.; ARTN e157035; https://qmro.qmul.ac.uk/xmlui/handle/123456789/103572 |
| DOI: |
10.1172/jci.insight.157035 |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/103572; https://doi.org/10.1172/jci.insight.157035 |
| Rights: |
This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. ; © 2022, Li et al. |
| Accession Number: |
edsbas.CC6AF39A |
| Database: |
BASE |