University of Oulu

Cronjé, H.T., Karhunen, V., Hovingh, G.K. et al. Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study. BMC Med 21, 158 (2023).

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk : a Mendelian randomization study

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Author: Cronjé, Héléne T.1; Karhunen, Ville2,3; Hovingh, G. Kees4,5;
Organizations: 1Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen, Denmark
2Faculty of Science, Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
3Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
4Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
5Global Chief Medical Office, Novo Nordisk, Copenhagen, Denmark
6Global Project Management, Global Drug Discovery, Novo Nordisk, Copenhagen, Denmark
7Rare Endocrine Disorders, Research and Early Development, Novo Nordisk, Copenhagen, Denmark
8Department of Experimental Medical Science, Lund University, 221 84, Lund, Sweden
9Vascular Biology, Research and Early Development, Novo Nordisk, Maaloev, Denmark
10Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark
11Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-08-21


Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework.

Methods: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome.

Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target.

Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.

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Series: BMC medicine
ISSN: 1741-7015
ISSN-E: 1741-7015
ISSN-L: 1741-7015
Volume: 21
Issue: 1
Article number: 158
DOI: 10.1186/s12916-023-02867-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: HTC is supported by the Novo Nordic Foundation Challenge Programme: Harnessing the Power of Big Data to Address the Societal Challenge of Aging (NNF17OC0027812). DG is supported by the British Heart Foundation Centre of Research Excellence at Imperial College London (RE/18/4/34215). VK is funded by Academy of Finland Profi 5 (Project 326291) and the European Union’s Horizon 2020 grant agreement (no. 848158; EarlyCause).
EU Grant Number: (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Copyright information: © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.