通过肾脏的多组学分析揭示高血压的遗传机制。
Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.
作者信息
Eales James M, Jiang Xiao, Xu Xiaoguang, Saluja Sushant, Akbarov Artur, Cano-Gamez Eddie, McNulty Michelle T, Finan Christopher, Guo Hui, Wystrychowski Wojciech, Szulinska Monika, Thomas Huw B, Pramanik Sanjeev, Chopade Sandesh, Prestes Priscilla R, Wise Ingrid, Evangelou Evangelos, Salehi Mahan, Shakanti Yusif, Ekholm Mikael, Denniff Matthew, Nazgiewicz Alicja, Eichinger Felix, Godfrey Bradley, Antczak Andrzej, Glyda Maciej, Król Robert, Eyre Stephen, Brown Jason, Berzuini Carlo, Bowes John, Caulfield Mark, Zukowska-Szczechowska Ewa, Zywiec Joanna, Bogdanski Pawel, Kretzler Matthias, Woolf Adrian S, Talavera David, Keavney Bernard, Maffia Pasquale, Guzik Tomasz J, O'Keefe Raymond T, Trynka Gosia, Samani Nilesh J, Hingorani Aroon, Sampson Matthew G, Morris Andrew P, Charchar Fadi J, Tomaszewski Maciej
机构信息
Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
出版信息
Nat Genet. 2021 May;53(5):630-637. doi: 10.1038/s41588-021-00835-w. Epub 2021 May 6.
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.
肾脏是与血压（BP）调节、高血压及抗高血压治疗密切相关的器官。然而，高血压易感性背后的基因介导肾脏机制仍知之甚少。我们整合了多达430个人类肾脏的基因型、基因表达、可变剪接和DNA甲基化谱，以表征全基因组关联研究（GWAS）中的血压指数变异对肾脏转录组和表观基因组的影响。我们发现了479个（58.3%）血压GWAS变异的肾脏靶点，并将49个血压GWAS肾脏基因与210种已获许可的药物进行了配对。我们的共定位和孟德尔随机化分析确定了179个独特的肾脏基因，有证据表明它们对血压有假定的因果效应。通过孟德尔随机化，我们还发现了血压对通常影响高血压患者的肾脏结局的作用。总体而言，我们的研究确定了与血压的遗传调控和高血压遗传易感性密切相关的基因变异、肾脏基因、分子机制和生物学途径。
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