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

Arthritis Rheumatol. 2023 Oct;75(10):1781-1792. doi: 10.1002/art.42538. Epub 2023 Aug 3.

Authors

Jie Zheng¹, Eleanor Wheeler², Maik Pietzner³, Till F M Andlauer⁴, Michelle S Yau⁵, April E Hartley⁶, Ben Michael Brumpton⁷, Humaira Rasheed⁸, John P Kemp⁹, Monika Frysz¹⁰, Jamie Robinson⁶, Sjur Reppe¹¹, Vid Prijatelj¹², Kaare M Gautvik¹³, Louise Falk³, Winfried Maerz¹⁴, Ingrid Gergei¹⁵, Patricia A Peyser¹⁶, Maryam Kavousi¹⁷, Paul S de Vries¹⁸, Clint L Miller¹⁹, Maxime Bos¹⁷, Sander W van der Laan²⁰, Rajeev Malhotra²¹, Markus Herrmann²², Hubert Scharnagl²², Marcus Kleber²³, George Dedoussis²⁴, Eleftheria Zeggini²⁵, Maria Nethander²⁶, Claes Ohlsson²⁷, Mattias Lorentzon²⁸, Nick Wareham², Claudia Langenberg³, Michael V Holmes²⁹, George Davey Smith⁶, Jonathan H Tobias¹⁰

Affiliations

¹ 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.
² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³ 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.
⁴ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁵ Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts.
⁶ MRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ MRC IEU, Bristol Medical School, University of Bristol, and Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
¹¹ 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.
¹² Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹³ Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
¹⁴ 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.
¹⁵ 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.
¹⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor.
¹⁷ Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
¹⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston.
¹⁹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville.
²⁰ Central Diagnostics Laboratory, Division of Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²¹ Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston.
²² Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
²³ SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
²⁴ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
²⁵ 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.
²⁶ 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.
²⁷ Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
²⁸ 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.
²⁹ 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.

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.

Publication types

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

MeSH terms

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

Abstract

Publication types

MeSH terms

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