Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans
Holdsworth, Gill; Staley, James R.; Hall, Peter; van Koeverden, Ian; Vangjeli, Ciara; Okoye, Remi; Boyce, Rogely W.; Turk, James R.; Armstrong, Martin; Wolfreys, Alison; Pasterkamp, Gerard
(2021) Journal of Bone and Mineral Research, volume 36, issue 7, pp. 1326 - 1339
(Article)
Abstract
Inhibition of sclerostin increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density, and bone strength and reduced fracture risk. In a clinical study of the sclerostin antibody romosozumab versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) adverse events driven
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by an increase in myocardial infarction (MI) and stroke was observed. To explore whether there was a potential mechanistic plausibility that sclerostin expression, or its inhibition, in atherosclerotic (AS) plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability in 94 carotid and 50 femoral AS plaques surgically collected from older female patients (mean age 69.6 ± 10.4 years). Sclerostin staining was absent in most plaques (67%), and when detected, it was of reduced intensity compared with normal aorta and was located in deeper regions of the plaque/wall but was not observed in areas considered relevant to plaque stability (fibrous cap and endothelium). Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenomewide association study (PheWAS). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between the presence of sclerostin, or its inhibition, in the vasculature and increased risk of serious cardiovascular events.
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Keywords: Aged, Aged, 80 and over, Alendronate, Bone Density, Cardiovascular Diseases/genetics, Down-Regulation, Female, Humans, Middle Aged, Plaque, Atherosclerotic/genetics, SCLEROSTIN, CARDIOVASCULAR, BONE MINERAL DENSITY, GENETICS, SOST, PHENOMEWIDE ASSOCIATION STUDY, Endocrinology, Diabetes and Metabolism, Orthopedics and Sports Medicine, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0884-0431
Publisher: Wiley-Blackwell
Note: Funding Information: The authors thank Dr Chris Paszty (Amgen Inc.) and Dr Jochen Dunkel (UCB Pharma) for their helpful support, and Petra van der Kraak (University Medical Centre Utrecht) for technical support to perform IHC staining of AS plaques. Summary statistics were downloaded from the NHGRI-EBI GWAS Catalog(48) for studies GCST006979, GCST006980,(32) GCST005194,(46) GCST005838, GCST005843,(42) GCST006414,(43) GCST009541,(45) GCST007517,(41) GCST008058, and GCST008064,(47) downloaded on June 25, 2020. Data on coronary artery disease and myocardial infarction have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.cardiogramplusc4d.org. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. We thank the MEGASTROKE authors; the author list is available at https://www.megastroke.org/authors.html. All summary genetic association results used are available in the public domain. Authors? roles: GH, PH, RO, RWB, JRT and GP: conceptualization and methodology for IHC study. RO: Scl-Ab investigations. PH, IVK, GH, and GP: formal analysis of IHC study data. GH, JRS, CV, AW, and MA: conceptualization for genetics analysis. JRS and CV: investigation and formal analysis for human genetic association studies. GH, JRS, PH, CV, and AW: original draft preparation. All co-authors reviewed and edited the final version of the submitted manuscript. Author contributions: GH: Conceptualization; formal analysis; methodology; writing-original draft; writing-review & editing. JRS: Conceptualization; formal analysis; investigation; writing-original draft; writing-review & editing. PH: Conceptualization; formal analysis; methodology; writing-original draft; writing-review & editing. IVK: Formal analysis; writing-review & editing. CV: Conceptualization; formal analysis; investigation; writing-original draft; writing-review & editing. RO: Investigation; writing-review & editing. RWB: Conceptualization; methodology; writing-review & editing. JT: Conceptualization; methodology; writing-review & editing. MA: Formal analysis; writing-review & editing. AW: Formal analysis; writing-original draft; writing-review & editing. GP: Conceptualization; formal analysis; methodology; writing-review & editing. Publisher Copyright: © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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