2024年9月10日，《自然—遗传学》杂志在线发表了美国科学家的一项最新研究成果。来自加州大学旧金山分校Jeremy F. Reiter等研究人员合作发现，肾小管上皮调控元件中的变异介导人类肾功能遗传差异的大部分。

研究人员对英国生物样本库中406504名个体进行了全基因组关联研究（GWAS），鉴定出影响中年成人肾功能的430个基因位点。为了研究这些基因位点影响的细胞类型，研究人员将GWAS与通过单细胞转座酶可接近染色质测序（scATAC-seq）鉴定的人类肾候选顺式调控元件（cCRE）进行了整合。

总体上，56%的肾功能遗传力定位于肾小管上皮cCRE，另外7%定位于肾小囊足细胞cCRE。因此，成人肾功能的大多数遗传差异是由这两种细胞类型中基因表达的改变所引起的。

通过增强子分析、等位基因特异性scATAC-seq和机器学习，研究人员发现许多肾功能变异改变了肾小管上皮cCRE的染色质可及性和功能。利用CRISPRi技术，研究人员确定了一些cCRE调控的基因，揭示了NDRG1、CCNB1和STC1在调控人类肾功能中的作用。

据了解，肾功能衰竭，即肾功能下降至无法维持生命的阈值以下，是导致发病率和死亡率的主要原因。

附：英文原文

Title: Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Author: Loeb, Gabriel B., Kathail, Pooja, Shuai, Richard W., Chung, Ryan, Grona, Reinier J., Peddada, Sailaja, Sevim, Volkan, Federman, Scot, Mader, Karl, Chu, Audrey Y., Davitte, Jonathan, Du, Juan, Gupta, Alexander R., Ye, Chun Jimmie, Shafer, Shawn, Przybyla, Laralynne, Rapiteanu, Radu, Ioannidis, Nilah M., Reiter, Jeremy F.

Issue&Volume: 2024-09-10

Abstract: Kidney failure, the decrease of kidney function below a threshold necessary to support life, is a major cause of morbidity and mortality. We performed a genome-wide association study (GWAS) of 406,504 individuals in the UK Biobank, identifying 430 loci affecting kidney function in middle-aged adults. To investigate the cell types affected by these loci, we integrated the GWAS with human kidney candidate cis-regulatory elements (cCREs) identified using single-cell assay for transposase-accessible chromatin sequencing (scATAC–seq). Overall, 56% of kidney function heritability localized to kidney tubule epithelial cCREs and an additional 7% to kidney podocyte cCREs. Thus, most heritable differences in adult kidney function are a result of altered gene expression in these two cell types. Using enhancer assays, allele-specific scATAC–seq and machine learning, we found that many kidney function variants alter tubule epithelial cCRE chromatin accessibility and function. Using CRISPRi, we determined which genes some of these cCREs regulate, implicating NDRG1, CCNB1 and STC1 in human kidney function.

DOI: 10.1038/s41588-024-01904-6

Source: https://www.nature.com/articles/s41588-024-01904-6