期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2114734119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The genetic architecture of chronic kidney disease (CKD) remains incompletely understood. Variants in the kidney-specific gene
UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD) and are associated with kidney function and the risk of CKD in the general population. We identified an intermediate-effect variant, p.Thr62Pro, detected in ∼1/1,000 individuals of European ancestry that showed a high genetic load in familial clusters of CKD and was associated with an odds ratio (OR) of approximately four for kidney failure in the 100,000 Genomes Project and the UK Biobank. Compared with canonical ADTKD mutations, p.Thr62Pro carriers displayed reduced disease severity and an intermediate trafficking defect. These findings complete the spectrum of
UMOD-associated kidney diseases and provide a paradigm for the genetic contribution to CKD.
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.
