An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

Olinger E, Schaeffer C, Kidd K, Elhassan EA, Cheng Y, Dufour I, Schiano G, Mabillard H, Pasqualetto E, Hofmann P, Fuster DG, Kistler AD, Wilson IJ, Kmoch S, Raymond L, Robert T, Eckardt KU, Bleyer AJ, Kottgen A, Conlon PJ, Wiesener M, Sayer JA, Rampoldi L, Devuyst O (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 119

Article Number: e2114734119

Journal Issue: 33

DOI: 10.1073/pnas.2114734119

Abstract

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 1025 to 1023. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Authors with CRIS profile

Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension Michael Wiesener Professur für Innere Medizin (Nephrologie)

Involved external institutions

Newcastle University GB United Kingdom (GB) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) IT Italy (IT) Universitätsklinikum Freiburg DE Germany (DE) Wake Forest School of Medicine US United States (USA) (US) Spital Thurgau AG CH Switzerland (CH) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Eurofins GSC Luxembourg LU Luxembourg (LU) Inselspital, Universitätsspital Bern CH Switzerland (CH) Assistance Publique Hopitaux de Marseille FR France (FR)

How to cite

APA:

Olinger, E., Schaeffer, C., Kidd, K., Elhassan, E.A., Cheng, Y., Dufour, I.,... Devuyst, O. (2022). An intermediate-effect size variant in UMOD confers risk for chronic kidney disease. Proceedings of the National Academy of Sciences of the United States of America, 119(33). https://doi.org/10.1073/pnas.2114734119

MLA:

Olinger, Eric, et al. "An intermediate-effect size variant in UMOD confers risk for chronic kidney disease." Proceedings of the National Academy of Sciences of the United States of America 119.33 (2022).

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