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.

Humans Genome-Wide Association Study Diabetes Mellitus, Type 2 / genetics Mendelian Randomization Analysis Atherosclerosis / genetics Myocardial Infarction / etiology Risk Factors Hypertension Polymorphism, Single Nucleotide

Journal

Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795

Informations de publication

Date de publication:
10 2023
Historique:
revised: 22 03 2023
received: 27 06 2022
accepted: 18 04 2023
pmc-release: 01 10 2024
medline: 23 10 2023
pubmed: 25 4 2023
entrez: 25 04 2023
Statut: ppublish

Résumé

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. 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. 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. 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.

Identifiants

DOI: 10.1002/art.42538 PMID: 37096546 PMC: PMC10586470
pubmed: 37096546
doi: 10.1002/art.42538
pmc: PMC10586470
mid: NIHMS1897628
doi:

Types de publication

Meta-Analysis Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1781-1792

Subventions

Organisme : Wellcome Trust
ID : 20378/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00006/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL162928
Pays : United States
Organisme : NIH HHS
ID : N01-AR-2-2261
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159514
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146860
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK072488
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148239
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR072571
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIH HHS
ID : N01-AR-2-2258
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR075356
Pays : United States
Organisme : NIH HHS
ID : N01-AR-2-2262
Pays : United States
Organisme : Wellcome Trust
ID : WT102215/2/13/2
Pays : United Kingdom
Organisme : NIH HHS
ID : N01-AR-2-2260
Pays : United States
Organisme : NIH HHS
ID : N01-AR-2-2259
Pays : United States
Organisme : Wellcome Trust
ID : WT088806
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT092830M
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL142809
Pays : United States

Informations de copyright

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

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Auteurs

Jie Zheng (J)

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic of China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.
ORCID: 0000-0002-6623-6839

Eleanor Wheeler (E)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Maik Pietzner (M)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.

Till F M Andlauer (TFM)

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Michelle S Yau (MS)

Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts.
ORCID: 0000-0002-0445-6334

April E Hartley (AE)

MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.
ORCID: 0000-0003-4932-1588

Ben Michael Brumpton (BM)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, and HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.

Humaira Rasheed (H)

MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK, and HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway, and Division of Medicine and Laboratory Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.

John P Kemp (JP)

MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK, and Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia, and The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.

Monika Frysz (M)

MRC IEU, Bristol Medical School, University of Bristol, and Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
ORCID: 0000-0001-5729-778X

Jamie Robinson (J)

MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.

Sjur Reppe (S)

Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital and Department of Plastic and Reconstructive Surgery, Oslo University Hospital and Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.

Vid Prijatelj (V)

Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
ORCID: 0000-0002-9463-3962

Kaare M Gautvik (KM)

Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.

Louise Falk (L)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.

Winfried Maerz (W)

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria, and SYNLAB Academy, SYNLAB Holding Deutschland GmbH and Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Ingrid Gergei (I)

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, and Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany.

Patricia A Peyser (PA)

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor.

Maryam Kavousi (M)

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Paul S de Vries (PS)

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston.

Clint L Miller (CL)

Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville.

Maxime Bos (M)

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Sander W van der Laan (SW)

Central Diagnostics Laboratory, Division of Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Rajeev Malhotra (R)

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston.

Markus Herrmann (M)

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

Hubert Scharnagl (H)

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
ORCID: 0000-0002-2750-006X

Marcus Kleber (M)

SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.

George Dedoussis (G)

Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.

Eleftheria Zeggini (E)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, and Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.
ORCID: 0000-0003-4238-659X

Maria Nethander (M)

Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg and Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Claes Ohlsson (C)

Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Mattias Lorentzon (M)

Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and Region Västra Götaland, Geriatric Medicine, Sahlgrenska University Hospital, Mölndal, Sweden, and Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia.

Nick Wareham (N)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Claudia Langenberg (C)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.

Michael V Holmes (MV)

MRC IEU, Bristol Medical School, University of Bristol, and Medical Research Council Population Health Research Unit, University of Oxford, and Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, and National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.

George Davey Smith (G)

MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.

Jonathan H Tobias (JH)

MRC IEU, Bristol Medical School, University of Bristol, and Musculoskeletal Research Unit, University of Bristol, Bristol, UK.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Techniques d'investigation › Analyse de randomisation mendélienne › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Artériopathies oblitérantes › Artériosclérose › Athérosclérose › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Nécrose › Infarctus › Infarctus du myocarde › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Hypertension artérielle › Lowering of Circulating Sclerostin May...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Lowering of Circulating Sclerostin May...