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

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Cronjé, Héléne T.University of Copenhagen (författare)

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

Artikel/kapitelEngelska2023

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2023

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LIBRIS-ID:oai:lup.lub.lu.se:44e9bf7c-6d1a-4bc6-a44c-ea768e2f12fb
https://lup.lub.lu.se/record/44e9bf7c-6d1a-4bc6-a44c-ea768e2f12fbURI
https://doi.org/10.1186/s12916-023-02867-xDOI

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Språk:engelska
Sammanfattning på:engelska

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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.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
Blood pressure
C-type natriuretic peptide
Cardiovascular disease
Genetic epidemiology
Mendelian randomization
NPR2
NPR3

Biuppslag (personer, institutioner, konferenser, titlar ...)

Karhunen, VilleUniversity of Oulu (författare)
Hovingh, G. KeesAcademic Medical Center of University of Amsterdam (AMC),Novo Nordisk A/S,University of Amsterdam (författare)
Coppieters, KenNovo Nordisk A/S (författare)
Lagerstedt, Jens O.Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine,Novo Nordisk A/S(Swepub:lu)med-jls (författare)
Nyberg, MichaelNovo Nordisk A/S (författare)
Gill, DipenderNovo Nordisk A/S,Imperial College London (författare)
University of CopenhagenUniversity of Oulu (creator_code:org_t)

Sammanhörande titlar

Ingår i:BMC Medicine21:11741-7015

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Av författaren/redakt...: Cronjé, Héléne T ...; Karhunen, Ville; Hovingh, G. Kees; Coppieters, Ken; Lagerstedt, Jens ...; Nyberg, Michael; visa fler...; Gill, Dipender; visa färre...

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Av lärosätet: Lunds universitet

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