英国曼彻斯特大学Maciej Tomaszewski团队通过肾脏多组学分析揭示高血压的遗传机制。该研究于2021年5月6日发表于国际一流学术期刊《自然—遗传学》。

研究人员整合了多达430个人类肾脏的基因型、基因表达、可变剪接和DNA甲基化图谱，用于表征来自全基因组关联研究（GWAS）的血压（BP）指标变体对肾脏转录组和表观基因组的影响。研究人员发现了479个（58.3％）BP-GWAS变体的肾脏靶标，并将49个BP-GWAS肾脏基因与210种授权药物配对。这些共定位和孟德尔随机分析确定了179个独特的肾脏基因，并有可能对BP造成了因果关系。

通过孟德尔随机化，研究人员还发现了BP对通常影响高血压患者肾脏结局的影响。总的来说，这项研究确定了遗传变异、肾脏基因、分子机制和与BP遗传调控关键相关的遗传途径和遗传的高血压易感性。

据悉，肾脏是与BP调节，高血压和抗高血压治疗关键相关的器官。然而，对高血压易感性的遗传介导的肾脏机制仍然知之甚少。

附：英文原文

Title: Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney

Author: James M. Eales, Xiao Jiang, Xiaoguang Xu, Sushant Saluja, Artur Akbarov, Eddie Cano-Gamez, Michelle T. McNulty, Christopher Finan, Hui Guo, Wojciech Wystrychowski, Monika Szulinska, Huw B. Thomas, Sanjeev Pramanik, Sandesh Chopade, Priscilla R. Prestes, Ingrid Wise, Evangelos Evangelou, Mahan Salehi, Yusif Shakanti, Mikael Ekholm, Matthew Denniff, Alicja Nazgiewicz, Felix Eichinger, Bradley Godfrey, Andrzej Antczak, Maciej Glyda, Robert Krl, Stephen Eyre, Jason Brown, Carlo Berzuini, John Bowes, Mark Caulfield, Ewa Zukowska-Szczechowska, Joanna Zywiec, Pawel Bogdanski, Matthias Kretzler, Adrian S. Woolf, David Talavera, Bernard Keavney, Pasquale Maffia, Tomasz J. Guzik, Raymond T. OKeefe, Gosia Trynka, Nilesh J. Samani, Aroon Hingorani, Matthew G. Sampson, Andrew P. Morris, Fadi J. Charchar, Maciej Tomaszewski

Issue&Volume: 2021-05-06

Abstract: The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension. Gene expression, alternative splicing and DNA methylation profiles from human kidney samples provide insights into the effects of common variants influencing blood pressure. Mendelian randomization uncovers the effects of blood pressure on renal outcomes.

DOI: 10.1038/s41588-021-00835-w

Source: https://www.nature.com/articles/s41588-021-00835-w