Ganji-Arjenaki Mahboube, Kamali Zoha, Sardari Soroush, de Borst Martin, Snieder Harold, Vaez Ahmad
Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Kidney Int Rep. 2024 Mar 13;9(6):1849-1859. doi: 10.1016/j.ekir.2024.03.001. eCollection 2024 Jun.
Blood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP.
Here, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wide association studies (GWAS) results to specific cell types of the mature human kidney. We used the largest single-stage BP genome-wide analysis to date, including up to 1,028,980 adults of European ancestry, and single-cell transcriptomic data from 14 mature human kidneys, with mean age of 41 years.
Our analyses prioritized myofibroblasts and endothelial cells, among the total of 33 annotated cell type, as specifically involved in BP regulation ( < 0.05/33, i.e., 0.001515). Enrichment of heritability for systolic BP (SBP) was observed in myofibroblast cells in mature human kidney cortex, and enrichment of heritability for diastolic BP (DBP) was observed in descending vasa recta and peritubular capillary endothelial cells as well as stromal myofibroblast cells. The new finding of myofibroblast, the significant cell type for both BP traits, was consistent in 8 replication efforts using 7 sets of independent data, including in human fetal kidney, in East-Asian (EAS) ancestry, using mouse single-cell RNA sequencing (scRNA-seq) data, and when using another prioritization method.
Our findings provide a solid basis for follow-up studies to further identify genes and mechanisms in myofibroblast cells that underlie the regulation of BP.
血压（BP）是一种高度可遗传的性状，迄今为止已确定了2000多个潜在的基因组位点。尽管肾脏起着关键作用，但对于参与血压遗传调控的特定细胞类型却知之甚少。
在此，我们应用分层连锁不平衡评分（LDSC）回归，将全基因组关联研究（GWAS）的血压结果与成熟人类肾脏的特定细胞类型联系起来。我们使用了迄今为止最大规模的单阶段血压全基因组分析，包括多达1028980名欧洲血统的成年人，以及来自14个平均年龄为41岁的成熟人类肾脏的单细胞转录组数据。
在总共33种注释细胞类型中，我们的分析将肌成纤维细胞和内皮细胞确定为特别参与血压调节的细胞类型（<0.05/33，即0.001515）。在成熟人类肾皮质的肌成纤维细胞中观察到收缩压（SBP）遗传力的富集，在直小血管降支、肾小管周围毛细血管内皮细胞以及基质肌成纤维细胞中观察到舒张压（DBP）遗传力的富集。肌成纤维细胞这一血压性状的重要细胞类型的新发现，在使用7组独立数据的8次重复研究中得到了证实，包括在人类胎儿肾脏、东亚（EAS）血统、使用小鼠单细胞RNA测序（scRNA-seq）数据以及使用另一种优先排序方法时。
我们的研究结果为后续研究提供了坚实的基础，以进一步确定肌成纤维细胞中构成血压调节基础的基因和机制。
