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

Author:

Zheng Jie1ORCID,Wheeler Eleanor2,Pietzner Maik3,Andlauer Till F. M.4,Yau Michelle S.5ORCID,Hartley April E.6ORCID,Brumpton Ben Michael7,Rasheed Humaira8,Kemp John P.9,Frysz Monika10ORCID,Robinson Jamie6,Reppe Sjur11,Prijatelj Vid12ORCID,Gautvik Kaare M.13,Falk Louise3,Maerz Winfried14,Gergei Ingrid15,Peyser Patricia A.16,Kavousi Maryam17,de Vries Paul S.18,Miller Clint L.19,Bos Maxime17,van der Laan Sander W.20,Malhotra Rajeev21,Herrmann Markus22,Scharnagl Hubert22ORCID,Kleber Marcus23,Dedoussis George24,Zeggini Eleftheria25ORCID,Nethander Maria26,Ohlsson Claes27,Lorentzon Mattias28,Wareham Nick2,Langenberg Claudia3,Holmes Michael V.29,Davey Smith George6,Tobias Jonathan H.10

Affiliation:

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...

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

ObjectiveIn this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.MethodsA 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.ResultsWe 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.ConclusionThis 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.image

Funder

European Research Area Network on Cardiovascular Diseases

National Heart, Lung, and Blood Institute

National Key Research and Development Program of China

Wellcome Trust

UK Medical Research Council

University of Bristol

NIH

National Health and Medical Research Council

Horizon 2020

American Heart Association

Publisher

Wiley

Subject

Immunology,Rheumatology,Immunology and Allergy

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