Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, and.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
JCI Insight. 2022 May 23;7(10):e157035. doi: 10.1172/jci.insight.157035.
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's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.
尿调蛋白(UMOD)是单基因和复杂形式肾脏疾病的主要风险基因。编码的肾脏特异性蛋白尿调蛋白在尿液中含量丰富,与慢性肾脏病、高血压和病原体防御有关。为了深入了解潜在的系统作用,我们使用互补的基于抗体和基于适配体的检测方法对循环尿调蛋白进行了全基因组筛选。我们分别检测到 3 个和 10 个不同的显著基因座。在基于抗体的结果与原发性人肾组织的功能基因组学数据(RNA-Seq、ATAC-Seq、Hi-C)整合时,UMOD 基因座上的上游变体显示出在合成尿调蛋白的肾细胞中具有不同的可及性和转录,这是观察到的顺式效应的基础。与复杂特征(包括慢性肾脏病和血压)的共同关联模式将 PRKAG2 基因座置于与 UMOD 相同的途径中。对第三个基于抗体的基因座 B4GALNT2 的实验验证表明,编码 N-乙酰半乳糖胺基转移酶的 p.Cys466Arg 变体具有失活效应,导致血清尿调蛋白水平升高。基于适配体的结果指向存在于尿调蛋白上的聚糖标记的酶及其在循环中的受体,表明该检测方法可用于研究尿调蛋白的复杂糖基化,而不仅仅是其定量水平。总的来说,我们的研究提供了对循环尿调蛋白及其新兴功能的深入了解。