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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)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Chronic Kidney Disease ; Genetics ; Nephrology ; Population Genetics

ISSN (print) / ISBN 2379-3708

e-ISSN 2379-3708

Journal JCI insight

Quellenangaben Volume: 7, Issue: 10, Article Number: e157035

Publisher Clarivate

Publishing Place Ann Arbor, Michigan

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)

Grants Medical Research Council