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Cited by 22Genetic Associations and EpidemiologyRenal Diseases and GlomerulopathiesChronic Kidney Disease and Diabetes

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

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Li, Yong, Cheng, Yurong, Consolato, Francesco, Schiano, Guglielmo, Chong, Michael R., Pietzner, Maik, Nguyen, Ngoc Quynh H., Scherer, Nora +35 more·2022·JCI Insight
DOI 10.1172/jci.insight.157035PMC PMC9220927
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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.

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  • Studies incorporating comparisons to MS protein measures, measures of gene transcript abundance, and/or functional validation have established cases where platform-discordant PAV cis-pQTL reflect differences in probe binding to genetically encoded isoforms, including for uromodulin and apolipoprotein-1.

    “While PAVs may certainly alter a protein’s overall abundance through impacts on protein stability and other mechanisms, studies incorporating comparisons to MS protein measures, measures of gene transcript abundance, and/or functional validation have established cases where platform-discordant PAV cis-pQTL reflect differences in probe binding to genetically encoded isoforms, including for uromodul”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [31]

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Authors
Li, Y., Cheng, Y., Consolato, F., Schiano, G., Chong, M. R., Pietzner, M., Nguyen, N. Q. H., Scherer, N., Biggs, M. L., Kleber, M. E., Haug, S., Göçmen, B., Pigeyre, M., Sekula, P., Steinbrenner, I., Schlosser, P., Joseph, C. B., Brody, J. A., Grams, M. E., Hayward, C., Schultheiss, U. T., Krämer, B. K., Kronenberg, F., Peters, A., Seissler, J., Steubl, D., Then, C., Wuttke, M., März, W., Eckardt, K.-U., Gieger, C., Boerwinkle, E., Psaty, B. M., Coresh, J., Oefner, P. J., Pare, G., Langenberg, C., Scherberich, J. E., Yu, B., Akilesh, S., Devuyst, O., Rampoldi, L., & Köttgen, A.
Affiliations
  • Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, and
  • University of Freiburg (DE)
  • IRCCS Ospedale San Raffaele (IT)
  • University of Zurich (CH)
  • Population Health Research Institute (CA)
  • University of Cambridge (GB)
  • The University of Texas Health Science Center at Houston (US)
  • University of Washington (US)
  • Heidelberg University (DE)
  • Johns Hopkins University (US)
  • Western General Hospital (GB)
  • Cardiovascular Health Research Unit, Department of Medicine, and
  • Innsbruck Medical University (AT)
  • Helmholtz Munich (DE)
  • LMU Klinikum (DE)
  • Tufts Medical Center (US)
  • Medical University of Graz (AT)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Baylor College of Medicine (US)
  • University of Regensburg (DE)
  • Population Health Research Institute and Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.
  • München Klinik Harlaching (DE)
Corresponding author
  • Rampoldi, Luca
  • Köttgen, Anna
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2022-05-23
Volume
7
Issue
10
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.157035
PMC
PMC9220927
OpenAlex
W4224240370
Cited by
22
References
3
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 6
FWCI
3.02
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Digital Access to Libraries (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Apollo (cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
  • University of Regensburg Publication Server (University of Regensburg)
Funders
  • Canadian Institutes of Health Research (Frederick Banting, Charles Best Canada Graduate Scholarships Doctoral Award)
  • Chinese Scholarship Council (Doctoral Scholarship)
  • MRC Human Genetics Unit programme (U. MC_UU_00007/10)
  • German Research Foundation (KO 3598/5-1,431984000 - SFB 1453,EXC-2189 – Project ID 390939984)
  • Medical Research Council (MC_UU_00006/1)
  • Italian Society of Nephrology (Adotta un progetto di ricerca)
  • Italian Ministry of Health (grant RF-2016-02362623)
  • University of Freiburg (EQUIP Program)
  • Deutsche Diabetes Gesellschaft (Support for C.T.)
  • German Federal Ministry of Education and Research (grant 01ZX1912B)
  • Swiss National Science Foundation (project grant 310030_189044)
  • Swiss National Centre of Competence in Research (The work of O.D., G.S.)
  • Kidney Control of Homeostasis (Kidney.CH)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
uromodulin, PRKAG2, B4GALNT2, N-acetylgalactosaminyltransferase, cis effect, chromatin accessibility, chronic kidney disease, blood pressure, complex traits, antibody-based assays, glycosylation, loss-of-function mutations
MeSH terms
Blood Pressure, Humans, Hypertension, Renal Insufficiency, Chronic, Genome-Wide Association Study, Uromodulin

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