@article {9103,
	title = {{Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases},
	journal = {JCI Insight},
	volume = {7},
	year = {2022},
	month = {05},
	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{\textquoteright}s complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.},
	author = {Li, Y. and Cheng, Y. and Consolato, F. and Schiano, G. and Chong, M. R. and Pietzner, M. and Nguyen, N. Q. H. and Scherer, N. and Biggs, M. L. and Kleber, M. E. and Haug, S. and G{\"o}{\c c}men, B. and Pigeyre, M. and Sekula, P. and Steinbrenner, I. and Schlosser, P. and Joseph, C. B. and Brody, J. A. and Grams, M. E. and Hayward, C. and Schultheiss, U. T. and Kr{\"a}mer, B. K. and Kronenberg, F. and Peters, A. and Seissler, J. and Steubl, D. and Then, C. and Wuttke, M. and M{\"a}rz, W. and Eckardt, K. U. and Gieger, C. and Boerwinkle, E. and Psaty, B. M. and Coresh, J. and Oefner, P. J. and Pare, G. and Langenberg, C. and Scherberich, J. E. and Yu, B. and Akilesh, S. and Devuyst, O. and Rampoldi, L. and K{\"o}ttgen, A.}
}
