Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

Rosa B Thorolfsdottir; Gardar Sveinbjornsson; Grimur Hjorleifsson Eldjarn; Hildur M Aegisdottir; Unnur Styrkarsdottir; Solveig Gretarsdottir; Valgerdur Steinthorsdottir; Vinicius Tragante; Asmundur Oddsson; Lilja Stefansdottir; Gudmar Thorleifsson; Gudmundur Einarsson; Hannes Helgason; Andrea B Jonsdottir; Sigurjon A Gudjonsson; Egil Ferkingstad; Søren Brunak; Nanna Brøns; Johan S Bundgaard; Mie T Bruun; Christian Erikstrup; Bitten Aagaard; Ole B Vesterager Pedersen; Kirstine L Sibilitz; Erik Sørensen; Jacob Træholt; Henrik Ullum; Chaoqun Zheng; Kirk U Knowlton; Lincoln D Nadauld; Sisse R Ostrowski; Henning Bundgaard; David O Arnar; Ingileif Jonsdottir; Anna Helgadottir; Unnur Thorsteinsdottir; Hilma Holm; Patrick Sulem; Daniel F Gudbjartsson; Kari Stefansson; DBDS Genomic Consortium

doi:10.1093/hmg/ddaf177

Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

Rosa B Thorolfsdottir^*, Gardar Sveinbjornsson, Grimur Hjorleifsson Eldjarn, Hildur M Aegisdottir, Unnur Styrkarsdottir, Solveig Gretarsdottir, Valgerdur Steinthorsdottir, Vinicius Tragante, Asmundur Oddsson, Lilja Stefansdottir, Gudmar Thorleifsson, Gudmundur Einarsson, Hannes Helgason, Andrea B Jonsdottir, Sigurjon A Gudjonsson, Egil Ferkingstad, Søren Brunak, Nanna Brøns, Johan S Bundgaard, Mie T BruunChristian Erikstrup, Bitten Aagaard, Ole B Vesterager Pedersen, Kirstine L Sibilitz, Erik Sørensen, Jacob Træholt, Henrik Ullum, Chaoqun Zheng, Kirk U Knowlton, Lincoln D Nadauld, Sisse R Ostrowski, Henning Bundgaard, David O Arnar, Ingileif Jonsdottir, Anna Helgadottir, Unnur Thorsteinsdottir, Hilma Holm, Patrick Sulem, Daniel F Gudbjartsson, Kari Stefansson, DBDS Genomic Consortium

^*Corresponding author af dette arbejde

Abstract

The causal effect of lower plasma sclerostin on cardiovascular disease (CVD) risk has previously been examined with the aim of investigating potential side effects of pharmacological sclerostin inhibition for treatment of osteoporosis. We explored the relationship between plasma sclerostin levels and CVDs and bone phenotypes using Mendelian randomization (MR) and correlation between plasma sclerostin levels and these outcomes. We used variants identified in genome-wide association studies of plasma sclerostin levels in large proteomic datasets from the UK Biobank (Olink) and Iceland (SomaScan) as instruments in two separate MR analyses. These analyses did not provide evidence of association between the effects of sequence variants on plasma sclerostin levels and their effects on CVDs and CVD risk factors (P > 0.05). Several of the instruments had heterogenic effects on bone phenotypes and causal estimates in MR were non-significant (P > 0.05/8). Plasma sclerostin levels correlated positively with coronary artery disease, myocardial infarction and CVD risk factors. Our results do not provide evidence supporting the hypothesis that lower plasma sclerostin levels increase CVD risk and suggest that plasma sclerostin levels are not a good surrogate for pharmacological inhibition.

Originalsprog	Engelsk
Artikelnummer	ddaf177
Tidsskrift	Human Molecular Genetics
Vol/bind	35
Udgave nummer	2
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddaf177
Status	Udgivet - 2026

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10.1093/hmg/ddaf177

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Thorolfsdottir, R. B., Sveinbjornsson, G., Hjorleifsson Eldjarn, G., Aegisdottir, H. M., Styrkarsdottir, U., Gretarsdottir, S., Steinthorsdottir, V., Tragante, V., Oddsson, A., Stefansdottir, L., Thorleifsson, G., Einarsson, G., Helgason, H., Jonsdottir, A. B., Gudjonsson, S. A., Ferkingstad, E., Brunak, S., Brøns, N., Bundgaard, J. S., ... DBDS Genomic Consortium (2026). Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition. Human Molecular Genetics, 35(2), Artikel ddaf177. https://doi.org/10.1093/hmg/ddaf177

Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition. / Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Hjorleifsson Eldjarn, Grimur et al.
I: Human Molecular Genetics, Bind 35, Nr. 2, ddaf177, 2026.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Thorolfsdottir, RB, Sveinbjornsson, G, Hjorleifsson Eldjarn, G, Aegisdottir, HM, Styrkarsdottir, U, Gretarsdottir, S, Steinthorsdottir, V, Tragante, V, Oddsson, A, Stefansdottir, L, Thorleifsson, G, Einarsson, G, Helgason, H, Jonsdottir, AB, Gudjonsson, SA, Ferkingstad, E, Brunak, S , Brøns, N , Bundgaard, JS, Bruun, MT, Erikstrup, C, Aagaard, B, Vesterager Pedersen, OB, Sibilitz, KL , Sørensen, E , Træholt, J, Ullum, H, Zheng, C, Knowlton, KU, Nadauld, LD, Ostrowski, SR , Bundgaard, H, Arnar, DO, Jonsdottir, I, Helgadottir, A, Thorsteinsdottir, U, Holm, H, Sulem, P, Gudbjartsson, DF, Stefansson, K & DBDS Genomic Consortium 2026, 'Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition', Human Molecular Genetics, bind 35, nr. 2, ddaf177. https://doi.org/10.1093/hmg/ddaf177

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title = "Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition",

abstract = "The causal effect of lower plasma sclerostin on cardiovascular disease (CVD) risk has previously been examined with the aim of investigating potential side effects of pharmacological sclerostin inhibition for treatment of osteoporosis. We explored the relationship between plasma sclerostin levels and CVDs and bone phenotypes using Mendelian randomization (MR) and correlation between plasma sclerostin levels and these outcomes. We used variants identified in genome-wide association studies of plasma sclerostin levels in large proteomic datasets from the UK Biobank (Olink) and Iceland (SomaScan) as instruments in two separate MR analyses. These analyses did not provide evidence of association between the effects of sequence variants on plasma sclerostin levels and their effects on CVDs and CVD risk factors (P > 0.05). Several of the instruments had heterogenic effects on bone phenotypes and causal estimates in MR were non-significant (P > 0.05/8). Plasma sclerostin levels correlated positively with coronary artery disease, myocardial infarction and CVD risk factors. Our results do not provide evidence supporting the hypothesis that lower plasma sclerostin levels increase CVD risk and suggest that plasma sclerostin levels are not a good surrogate for pharmacological inhibition.",

author = "Thorolfsdottir, {Rosa B} and Gardar Sveinbjornsson and {Hjorleifsson Eldjarn}, Grimur and Aegisdottir, {Hildur M} and Unnur Styrkarsdottir and Solveig Gretarsdottir and Valgerdur Steinthorsdottir and Vinicius Tragante and Asmundur Oddsson and Lilja Stefansdottir and Gudmar Thorleifsson and Gudmundur Einarsson and Hannes Helgason and Jonsdottir, {Andrea B} and Gudjonsson, {Sigurjon A} and Egil Ferkingstad and S{\o}ren Brunak and Nanna Br{\o}ns and Bundgaard, {Johan S} and Bruun, {Mie T} and Christian Erikstrup and Bitten Aagaard and {Vesterager Pedersen}, {Ole B} and Sibilitz, {Kirstine L} and Erik S{\o}rensen and Jacob Tr{\ae}holt and Henrik Ullum and Chaoqun Zheng and Knowlton, {Kirk U} and Nadauld, {Lincoln D} and Ostrowski, {Sisse R} and Henning Bundgaard and Arnar, {David O} and Ingileif Jonsdottir and Anna Helgadottir and Unnur Thorsteinsdottir and Hilma Holm and Patrick Sulem and Gudbjartsson, {Daniel F} and Kari Stefansson and Maria Didriksen and Joseph Dowsett and Bjarke Feenstra and Frank Geller and Hansen, {Thomas Folkmann} and {Helenius Mikkelsen}, Dorte and Stemann, {Jakob Hjorth Von} and Schork, {Andrew J} and Christina Mikkelsen and Ostrowski, {Sisse Rye} and Michael Schwinn and Erik S{\o}rensen and Th{\o}rner, {Lise Wegner} and Werge, {Thomas Mears} and Alfonso Buil and Mette Kongstad and Janna Nissen and {DBDS Genomic Consortium}",

note = "{\textcopyright} The Author(s) 2025. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].",

year = "2026",

doi = "10.1093/hmg/ddaf177",

language = "English",

volume = "35",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "2",

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TY - JOUR

T1 - Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

AU - Thorolfsdottir, Rosa B

AU - Sveinbjornsson, Gardar

AU - Hjorleifsson Eldjarn, Grimur

AU - Aegisdottir, Hildur M

AU - Styrkarsdottir, Unnur

AU - Gretarsdottir, Solveig

AU - Steinthorsdottir, Valgerdur

AU - Tragante, Vinicius

AU - Oddsson, Asmundur

AU - Stefansdottir, Lilja

AU - Thorleifsson, Gudmar

AU - Einarsson, Gudmundur

AU - Helgason, Hannes

AU - Jonsdottir, Andrea B

AU - Gudjonsson, Sigurjon A

AU - Ferkingstad, Egil

AU - Brunak, Søren

AU - Brøns, Nanna

AU - Bundgaard, Johan S

AU - Bruun, Mie T

AU - Erikstrup, Christian

AU - Aagaard, Bitten

AU - Vesterager Pedersen, Ole B

AU - Sibilitz, Kirstine L

AU - Sørensen, Erik

AU - Træholt, Jacob

AU - Ullum, Henrik

AU - Zheng, Chaoqun

AU - Knowlton, Kirk U

AU - Nadauld, Lincoln D

AU - Ostrowski, Sisse R

AU - Bundgaard, Henning

AU - Arnar, David O

AU - Jonsdottir, Ingileif

AU - Helgadottir, Anna

AU - Thorsteinsdottir, Unnur

AU - Holm, Hilma

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F

AU - Stefansson, Kari

AU - DBDS Genomic Consortium

A2 - Didriksen, Maria

A2 - Dowsett, Joseph

A2 - Feenstra, Bjarke

A2 - Geller, Frank

A2 - Hansen, Thomas Folkmann

A2 - Helenius Mikkelsen, Dorte

A2 - Stemann, Jakob Hjorth Von

A2 - Schork, Andrew J

A2 - Mikkelsen, Christina

A2 - Ostrowski, Sisse Rye

A2 - Schwinn, Michael

A2 - Sørensen, Erik

A2 - Thørner, Lise Wegner

A2 - Werge, Thomas Mears

A2 - Buil, Alfonso

A2 - Kongstad, Mette

A2 - Nissen, Janna

N1 - © The Author(s) 2025. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

PY - 2026

Y1 - 2026

N2 - The causal effect of lower plasma sclerostin on cardiovascular disease (CVD) risk has previously been examined with the aim of investigating potential side effects of pharmacological sclerostin inhibition for treatment of osteoporosis. We explored the relationship between plasma sclerostin levels and CVDs and bone phenotypes using Mendelian randomization (MR) and correlation between plasma sclerostin levels and these outcomes. We used variants identified in genome-wide association studies of plasma sclerostin levels in large proteomic datasets from the UK Biobank (Olink) and Iceland (SomaScan) as instruments in two separate MR analyses. These analyses did not provide evidence of association between the effects of sequence variants on plasma sclerostin levels and their effects on CVDs and CVD risk factors (P > 0.05). Several of the instruments had heterogenic effects on bone phenotypes and causal estimates in MR were non-significant (P > 0.05/8). Plasma sclerostin levels correlated positively with coronary artery disease, myocardial infarction and CVD risk factors. Our results do not provide evidence supporting the hypothesis that lower plasma sclerostin levels increase CVD risk and suggest that plasma sclerostin levels are not a good surrogate for pharmacological inhibition.

AB - The causal effect of lower plasma sclerostin on cardiovascular disease (CVD) risk has previously been examined with the aim of investigating potential side effects of pharmacological sclerostin inhibition for treatment of osteoporosis. We explored the relationship between plasma sclerostin levels and CVDs and bone phenotypes using Mendelian randomization (MR) and correlation between plasma sclerostin levels and these outcomes. We used variants identified in genome-wide association studies of plasma sclerostin levels in large proteomic datasets from the UK Biobank (Olink) and Iceland (SomaScan) as instruments in two separate MR analyses. These analyses did not provide evidence of association between the effects of sequence variants on plasma sclerostin levels and their effects on CVDs and CVD risk factors (P > 0.05). Several of the instruments had heterogenic effects on bone phenotypes and causal estimates in MR were non-significant (P > 0.05/8). Plasma sclerostin levels correlated positively with coronary artery disease, myocardial infarction and CVD risk factors. Our results do not provide evidence supporting the hypothesis that lower plasma sclerostin levels increase CVD risk and suggest that plasma sclerostin levels are not a good surrogate for pharmacological inhibition.

U2 - 10.1093/hmg/ddaf177

DO - 10.1093/hmg/ddaf177

M3 - Journal article

C2 - 41324467

SN - 0964-6906

VL - 35

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

M1 - ddaf177

ER -

Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

Abstract

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