An intermediate effect size variant in UMOD confers risk for chronic kidney disease
An intermediate effect size variant in UMOD confers risk for chronic kidney disease
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UMOD 的中间效应大小变异会带来慢性肾病的风险
DOI：
10.1101/2021.09.27.21263789
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Olinger E
中科院分区：
文献类型：
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作者：
Olinger E
肾脏特异性基因UMOD编码尿调素，尿调素是正常尿液中排泄的最丰富的蛋白质。UMOD中罕见的大效应变异导致常染色体显性肾小管间质性肾病（ADTKD），而普通人群中常见的低影响变异与肾功能和慢性肾病（CKD）风险密切相关。目前尚不清楚UMOD中的中间效应变异是否会导致CKD。在此，使用大人群和ADTKD队列鉴定候选的中间效应UMOD变体。使用细胞模型、计算机模拟、患者样本以及国际数据库和生物库研究了生物学和表型效应。在ADTKD中报告的8个UMOD错义变体存在于基因组聚合数据库（gnomAD）中，次要等位基因频率（MAF）范围为10− 5至10−3。其中，错义变体p.Thr62Pro在欧洲血统的1000/1000个体中被检测到，在CKD的家族性集群中显示不完全的突变，但具有高遗传负荷，并且在100个个体中与肾衰竭相关，000基因组计划（比值比[OR] = 3.99 [1.84至8.98]）和英国生物库（OR = 4.12 [1.32至12.85]）。与典型的ADTKD突变相比，p.Thr62Pro携带者显示出疾病严重程度降低，CKD进展较慢，尿尿调蛋白水平中等程度降低，与体外中等运输缺陷和适度诱导内质网（ER）应激一致。鉴定一个中间效应UMOD变异体可以完善UMOD相关肾脏疾病的谱，并为ADTKD的机制和CKD的遗传结构提供深入的了解。
The kidney-specific geneUMODencodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants inUMODcause 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 inUMODcontribute to CKD. Here, candidate intermediate-effectUMODvariants 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. EightUMODmissense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10−5to 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-effectUMODvariant completes the spectrum ofUMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.