Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases
Yong Li, et al.
Yong Li, et al.
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Research Article Genetics Nephrology

Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases

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.

Authors

Yong Li, Yurong Cheng, Francesco Consolato, Guglielmo Schiano, Michael R. Chong, Maik Pietzner, Ngoc Quynh H. Nguyen, Nora Scherer, Mary L. Biggs, Marcus E. Kleber, Stefan Haug, Burulça Göçmen, Marie Pigeyre, Peggy Sekula, Inga Steinbrenner, Pascal Schlosser, Christina B. Joseph, Jennifer A. Brody, Morgan E. Grams, Caroline Hayward, Ulla T. Schultheiss, Bernhard K. Krämer, Florian Kronenberg, Annette Peters, Jochen Seissler, Dominik Steubl, Cornelia Then, Matthias Wuttke, Winfried März, Kai-Uwe Eckardt, Christian Gieger, Eric Boerwinkle, Bruce M. Psaty, Josef Coresh, Peter J. Oefner, Guillaume Pare, Claudia Langenberg, Jürgen E. Scherberich, Bing Yu, Shreeram Akilesh, Olivier Devuyst, Luca Rampoldi, Anna Köttgen

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Figure 4

Biological context of genes associated with circulating uromodulin and conceptual model.

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Biological context of genes associated with circulating uromodulin and c...
(A) Schematic of antibody- and aptamer-based measurement of circulating uromodulin. (B) Dot plot shows Gene Ontology (GO) terms — grouped into 3 categories (BP, biological process; MF, molecular function; CC, cellular component) — and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched for uromodulin-associated genes from the aptamer assay on the y axis. The x axis shows the proportion of the genes in the corresponding GO term or KEGG pathway. Only terms and pathways with more than 2 uromodulin-associated genes are displayed. The color intensity of the dots scales with the –log10(Benjamini-Hochberg–adjusted P value). (C) Conceptual model placing the most likely causal genes associated with circulating uromodulin into their biological context. Loci detected with the aptamer assay predominantly affect differential synthesis or recognition of glycan marks present on uromodulin. Gal, galactose; Glc, glucose; NAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid.