PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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.* ; Paré, G.* ; Langenberg, C.* ; Scherberich, J.E.* ; Yu, B.* ; Akilesh, S.* ; Devuyst, O.* ; Rampoldi, L.* ; Köttgen, A.*

Genome-wide studies reveal factors associated with circulating uromodulin and its relations with complex diseases.

JCI insight 7:e157035 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 (N=13,985) and aptamer-based (N=18,070) assays. We detected 3 and 10 distinct significant (p<5e-8) 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 highlights 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, place the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, shows that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase has a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results point 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 new insights into circulating uromodulin and its emerging functions.
Impact Factor
Scopus SNIP
Scopus
Cited By
Altmetric
9.484
0.000
1
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Chronic Kidney Disease ; Genetics ; Nephrology ; Population Genetics
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Zeitschrift JCI insight
Quellenangaben Band: 7, Heft: 10, Seiten: , Artikelnummer: e157035 Supplement: ,
Verlag Clarivate
Verlagsort Ann Arbor, Michigan
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504000-010
G-504091-004
Förderungen Medical Research Council
DOI 10.1172/jci.insight.157035
WOS ID WOS:000805409200001
PubMed ID 35446786
Erfassungsdatum 2022-07-04
[➜Korrektur melden]