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Xu, X.* ; Khunsriraksakul, C.* ; Eales, J.M.* ; Rubin, S.* ; Scannali, D.* ; Saluja, S.* ; Talavera, D.* ; Markus, H.* ; Wang, L.* ; Drzal, M.* ; Maan, A.* ; Lay, A.C.* ; Prestes, P.R.* ; Regan, J.* ; Diwadkar, A.R.* ; Denniff, M.* ; Rempega, G.* ; Ryszawy, J.* ; Król, R.* ; Dormer, J.P.* ; Szulinska, M.* ; Walczak, M.* ; Antczak, A.* ; Matias-Garcia, P.R. ; Waldenberger, M. ; Woolf, A.S.* ; Keavney, B.* ; Zukowska-Szczechowska, E.* ; Wystrychowski, W.* ; Zywiec, J.* ; Bogdanski, P.* ; Danser, A.H.J.* ; Samani, N.J.* ; Guzik, T.J.* ; Morris, A.P.* ; Liu, D.J.* ; Charchar, F.J.* ; Tomaszewski, M.*

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

Nat. Commun. 15:2359 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Messenger-rna Profiles; Mendelian Randomization; Instrumental Variables; Overriding Dominance; Connectivity Map; Angiotensin-ii; Expression; Variants; Mechanisms
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 2359 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504091-001
Grants NIH
French Society of Hypertension (SFHTA)
Health Innovation Manchester
University of Manchester Wellcome Institutional Strategic Support Funding
NIHR Manchester Biomedical Research Centre
Kidney Research UK
British Heart Foundation
French Hypertension Research Foundation (FRHTA)
Translation Manchester and Health Innovation Manchester
MRC-NIHR UK Rare Disease Research Platform
Victoria Fellowship, Australia
National Institutes of Health
British Heart Foundation (BHF)
DOI 10.1038/s41467-024-46132-y
WOS ID 001187872900016
Scopus ID 85188116760
PubMed ID 38504097
Erfassungsdatum 2024-04-11
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