Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization

Jie Zheng; Eleanor Wheeler; Maik Pietzner; Till F M Andlauer; Michelle S Yau; April E Hartley; Ben Michael Brumpton; Humaira Rasheed; John P Kemp; Monika Frysz; Jamie Robinson; Sjur Reppe; Vid Prijatelj; Kaare M Gautvik; Louise Falk; Winfried Maerz; Ingrid Gergei; Patricia A Peyser; Maryam Kavousi; Paul S de Vries; Clint L Miller; Maxime Bos; Sander W van der Laan; Rajeev Malhotra; Markus Herrmann; Hubert Scharnagl; Marcus Kleber; George Dedoussis; Eleftheria Zeggini; Maria Nethander; Claes Ohlsson; Mattias Lorentzon; Nick Wareham; Claudia Langenberg; Michael V Holmes; George Davey Smith; Jonathan H Tobias

doi:10.1002/art.42538

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization

Jie Zheng^*, Eleanor Wheeler, Maik Pietzner, Till F M Andlauer, Michelle S Yau, April E Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatelj, Kaare M Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A Peyser, Maryam Kavousi, Paul S de VriesClint L Miller, Maxime Bos, Sander W van der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V Holmes, George Davey Smith, Jonathan H Tobias

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

19 Citations (Scopus)

Abstract

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.

METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.

RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.

CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

Original language	English
Pages (from-to)	1781-1792
Number of pages	12
Journal	Arthritis and Rheumatology
Volume	75
Issue number	10
Early online date	3 Aug 2023
DOIs	https://doi.org/10.1002/art.42538
Publication status	Published - 28 Sept 2023

Bibliographical note

Funding Information:
We are extremely grateful to all the families who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Publisher Copyright:
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

Research Groups and Themes

Bristol Population Health Science Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Zheng, J., Wheeler, E., Pietzner, M., Andlauer, T. F. M., Yau, M. S., Hartley, A. E., Brumpton, B. M., Rasheed, H., Kemp, J. P., Frysz, M., Robinson, J., Reppe, S., Prijatelj, V., Gautvik, K. M., Falk, L., Maerz, W., Gergei, I., Peyser, P. A., Kavousi, M., ... Tobias, J. H. (2023). Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization. Arthritis and Rheumatology, 75(10), 1781-1792. https://doi.org/10.1002/art.42538

@article{6fd87df752fd465eb74dad178c168b49,

title = "Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization",

abstract = "OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.",

author = "Jie Zheng and Eleanor Wheeler and Maik Pietzner and Andlauer, {Till F M} and Yau, {Michelle S} and Hartley, {April E} and Brumpton, {Ben Michael} and Humaira Rasheed and Kemp, {John P} and Monika Frysz and Jamie Robinson and Sjur Reppe and Vid Prijatelj and Gautvik, {Kaare M} and Louise Falk and Winfried Maerz and Ingrid Gergei and Peyser, {Patricia A} and Maryam Kavousi and {de Vries}, {Paul S} and Miller, {Clint L} and Maxime Bos and {van der Laan}, {Sander W} and Rajeev Malhotra and Markus Herrmann and Hubert Scharnagl and Marcus Kleber and George Dedoussis and Eleftheria Zeggini and Maria Nethander and Claes Ohlsson and Mattias Lorentzon and Nick Wareham and Claudia Langenberg and Holmes, {Michael V} and {Davey Smith}, George and Tobias, {Jonathan H}",

note = "Funding Information: We are extremely grateful to all the families who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Publisher Copyright: {\textcopyright} 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2023",

month = sep,

day = "28",

doi = "10.1002/art.42538",

language = "English",

volume = "75",

pages = "1781--1792",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "Wiley",

number = "10",

}

Zheng, J, Wheeler, E, Pietzner, M, Andlauer, TFM, Yau, MS, Hartley, AE, Brumpton, BM, Rasheed, H, Kemp, JP, Frysz, M, Robinson, J, Reppe, S, Prijatelj, V, Gautvik, KM, Falk, L, Maerz, W, Gergei, I, Peyser, PA, Kavousi, M, de Vries, PS, Miller, CL, Bos, M, van der Laan, SW, Malhotra, R, Herrmann, M, Scharnagl, H, Kleber, M, Dedoussis, G, Zeggini, E, Nethander, M, Ohlsson, C, Lorentzon, M, Wareham, N, Langenberg, C, Holmes, MV, Davey Smith, G & Tobias, JH 2023, 'Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization', Arthritis and Rheumatology, vol. 75, no. 10, pp. 1781-1792. https://doi.org/10.1002/art.42538

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization. / Zheng, Jie; Wheeler, Eleanor; Pietzner, Maik et al.
In: Arthritis and Rheumatology, Vol. 75, No. 10, 28.09.2023, p. 1781-1792.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors

T2 - Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization

AU - Zheng, Jie

AU - Wheeler, Eleanor

AU - Pietzner, Maik

AU - Andlauer, Till F M

AU - Yau, Michelle S

AU - Hartley, April E

AU - Brumpton, Ben Michael

AU - Rasheed, Humaira

AU - Kemp, John P

AU - Frysz, Monika

AU - Robinson, Jamie

AU - Reppe, Sjur

AU - Prijatelj, Vid

AU - Gautvik, Kaare M

AU - Falk, Louise

AU - Maerz, Winfried

AU - Gergei, Ingrid

AU - Peyser, Patricia A

AU - Kavousi, Maryam

AU - de Vries, Paul S

AU - Miller, Clint L

AU - Bos, Maxime

AU - van der Laan, Sander W

AU - Malhotra, Rajeev

AU - Herrmann, Markus

AU - Scharnagl, Hubert

AU - Kleber, Marcus

AU - Dedoussis, George

AU - Zeggini, Eleftheria

AU - Nethander, Maria

AU - Ohlsson, Claes

AU - Lorentzon, Mattias

AU - Wareham, Nick

AU - Langenberg, Claudia

AU - Holmes, Michael V

AU - Davey Smith, George

AU - Tobias, Jonathan H

N1 - Funding Information: We are extremely grateful to all the families who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Publisher Copyright: © 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

PY - 2023/9/28

Y1 - 2023/9/28

N2 - OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

AB - OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.

U2 - 10.1002/art.42538

DO - 10.1002/art.42538

M3 - Article (Academic Journal)

C2 - 37096546

SN - 2326-5191

VL - 75

SP - 1781

EP - 1792

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 10

ER -

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

Access to Document

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this