Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets

Xiaoguang Xu, Chachrit Khunsriraksakul, James M. Eales, Sebastien Rubin, David Scannali, Sushant Saluja, David Talavera, Havell Markus, Lida Wang, Maciej Drzal, Akhlaq Maan, Abigail C. Lay, Priscilla R. Prestes, Jeniece Regan, Avantika R. Diwadkar, Matthew Denniff, Grzegorz Rempega, Jakub Ryszawy, Robert Król, John P. Dormer, Monika Szulinska, Marta Walczak, Andrzej Antczak, Pamela R. Matías-García, Melanie Waldenberger, Adrian S. Woolf, Bernard Keavney, Ewa Zukowska-Szczechowska, Wojciech Wystrychowski, Joanna Zywiec, Pawel Bogdanski, A. H. Jan Danser, Nilesh J. Samani, Tomasz J. Guzik, Andrew P. Morris, Dajiang J. Liu, Fadi J. Charchar and Maciej Tomaszewski ()
Additional contact information
Xiaoguang Xu: Faculty of Medicine, Biology and Health, University of Manchester
Chachrit Khunsriraksakul: Penn State College of Medicine
James M. Eales: Faculty of Medicine, Biology and Health, University of Manchester
Sebastien Rubin: Faculty of Medicine, Biology and Health, University of Manchester
David Scannali: Faculty of Medicine, Biology and Health, University of Manchester
Sushant Saluja: Faculty of Medicine, Biology and Health, University of Manchester
David Talavera: Faculty of Medicine, Biology and Health, University of Manchester
Havell Markus: Penn State College of Medicine
Lida Wang: Penn State College of Medicine
Maciej Drzal: Faculty of Medicine, Biology and Health, University of Manchester
Akhlaq Maan: Faculty of Medicine, Biology and Health, University of Manchester
Abigail C. Lay: Faculty of Medicine, Biology and Health, University of Manchester
Priscilla R. Prestes: Federation University Australia
Jeniece Regan: Penn State College of Medicine
Avantika R. Diwadkar: Penn State College of Medicine
Matthew Denniff: University of Leicester
Grzegorz Rempega: Medical University of Silesia
Jakub Ryszawy: Medical University of Silesia
Robert Król: Vascular and Transplant Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia
John P. Dormer: University Hospitals of Leicester
Monika Szulinska: Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences
Marta Walczak: Metabolic Disorders and Arterial Hypertension, Poznan University of Medical Sciences
Andrzej Antczak: Karol Marcinkowski University of Medical Sciences
Pamela R. Matías-García: Helmholtz Center Munich
Melanie Waldenberger: Helmholtz Center Munich
Adrian S. Woolf: Faculty of Biology, Medicine and Health, University of Manchester
Bernard Keavney: Faculty of Medicine, Biology and Health, University of Manchester
Ewa Zukowska-Szczechowska: Silesian Medical College
Wojciech Wystrychowski: Vascular and Transplant Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia
Joanna Zywiec: Diabetology and Nephrology, Zabrze, Medical University of Silesia
Pawel Bogdanski: Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences
A. H. Jan Danser: Division of Pharmacology and Vascular Medicine, Erasmus Medical Centre
Nilesh J. Samani: University of Leicester
Tomasz J. Guzik: Jagiellonian University Medical College
Andrew P. Morris: Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester
Dajiang J. Liu: Penn State College of Medicine
Fadi J. Charchar: Federation University Australia
Maciej Tomaszewski: Faculty of Medicine, Biology and Health, University of Manchester

Nature Communications, 2024, vol. 15, issue 1, 1-29

Abstract: Abstract Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Date: 2024
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DOI: 10.1038/s41467-024-46132-y

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