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

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 10 −5 to 10 −3 . 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.

Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

“…First, the transcriptional profiles revealed a canonical signature of ADTKD-UMOD progression, i.e., inflammation, fibrosis, and kidney failure in the Umod R186S kidneys, contrasting with an increased expression of genes involved in protein folding in the Umod C171Y kidneys. The changes driven by the R186S mutation are in line with the emerging role of ER proteostasis in kidney disease, as evidenced for intermediate-effect size variants in UMOD (Olinger et al, 2022) and for mutations in MUC1 also associated with ADTKD (Dvela-Levitt et al, 2019). Notably, Umod R186S kidneys show increased expression of the key autophagy markers SQSTM1 and ATG5.…”

Monogenic Kidney Diseases in Kidney Transplantation

“…Mounting evidence suggests that variants in important genes are involved in a spectrum of kidney diseases, ranging from large-effect to small-effect sizes responsible for monogenic diseases or complex disorders including CKD, respectively. 159 , 160 Based on their prevalence, these variants can be identified by massive parallel sequencing and other modalities of genetic testing or by genome-wide association studies. As described above, genetic testing has a tremendous potential for impacting both the pre-KT and post-KT phases.…”

Hypoxia controls expression of kidney-pathogenicMUC1variants

“…Genetic alterations comprising common low-effect to rare large-impact variants of kidney disease genes such as UMOD or MUC1 determine the susceptibility to the development of CKD ( Trudu et al, 2013 ; Olinger et al, 2020 ; Olinger et al, 2022 ). However, the broad heterogeneity observed in the course of CKD suggests a strong involvement of environmental factors in addition to genetic predisposition.…”