A genome-wide association analysis (GWAS) of the population with mutation of sclerostin in UK Biobank revealed a strong correlation between mutations in loop2, a specific structural region of sclerostin, and abnormal symptoms associated with cardiovascular atherosclerosis, through collaboration from Professor Daqing Ma (the member of Clinical and Veterinary Science of The Academy of Europe), Imperial College London, UK, Professor Zhang Ge, Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, and Professor Lyu Aiping (the member of Clinical and Veterinary Science of The Academy of Europe), Director, Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University. A genome-wide association analysis (GWAS) of the sclerostin mutant population in UK Biobank revealed a strong association between mutations in a specific structural region of the sclerostin protein, loop2, and abnormal symptoms associated with cardiovascular atherosclerosis.
UK Biobank is a large-scale, long-term biobank project in the UK, started in 2006 to study the influence of genetic and environmental factors on disease progression, containing genetic and health information on 500,000 participants. Sclerostin has an inhibitory effect on bone formation and a corresponding therapeutic monoclonal antibody to sclerostin protein has been successfully marketed to promote bone formation and reverse post-menopausal osteoporosis but has also been found to have serious non-negligible atherosclerosis-related cardiovascular risks. The US FDA and European EMA restricted the use of this monoclonal antibody for clinical reversal of osteoporosis to one year only; the EMA also strictly limits the use of this monoclonal antibody to patients with osteoporosis without a history of cardiovascular disease. Sclerostin monoclonal antibody mainly acts on the structural regions of sclerostin, loop2 and loop3. To gain insight into the association of specific structural regions of sclerostin with cardiovascular risk, researchers from Imperial College of Science and Technology and Hong Kong Baptist University collaborated to conduct a genome-wide association analysis (GWAS) of UK Biobank to screen for aberrant sites in specific structural regions of sclerostin that may be associated with cardiovascular risk. This study identified novel risk genetic variants in the sclerostin loop2 region that were more significantly associated with abnormal cardiovascular atherosclerosis-related symptoms than variants in other regions of sclerostin.
This study also supported the findings of the joint research team of Professor Zhang Ge from Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases at Hong Kong Baptist University, Professor Yu Yuanyuan from the Guangdong-Hong Kong-Macao Greater Bay Area International Collaboration Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP), and Chair Professor Lyu Aiping (Member of the European Academy of Clinical Sciences) from the Institute of Integrative Bioinformatics and Translational Sciences at Hong Kong Baptist University in a transgenic animal model that the loop3, a specific structural region of the sclerostin protein, is not involved in the cardioprotective effects of sclerostin (Yu Y, et al. Nat Commun 2022; Wang L, et al. Theranostics 2022; Yu S, et al. Acta Pharm Sin B 2022).
The molecular genetic studies of the above clinical sample pools and the molecular mechanisms in transgenic animal models are important for the development of a new generation of sclerostin inhibitors with cardiovascular safety to reverse osteoporosis, i.e., the need to precisely target the loop3 structural region of the sclerostin protein and circumvent the loop2 structural region. It also suggested new research directions for understanding the molecular mechanisms of how sclerostin proteins protect against cardiovascular disease.
Dr Ma is the member of Clinical and Veterinary Science of The Academy of Europe, Macintosh Chair Professor at Imperial college London, Director of the Anaesthesia Research Centre in the Department of Surgery and Medical Oncology at Imperial College Westminster Hospital, and President Elect of the British Society of Chinese Life Scientists, Executive Vice President of the British Chinese Professors' Association, Qiuishi Scholar Chair Professor at Zhejiang University, and Kennedy Visiting Professor at Hong Kong Baptist University. Professor Ma's academic contributions include: 1) pioneering research on the protective effects of inert gases (Xenon and argon) on the brain, lungs and kidneys (including kidney transplants), and maintaining a world-renowned position in this field; 2) based on Professor Ma's research findings on the molecular mechanisms of the cytoprotective effects of Xenon and argon, the World Anti-Doping Organisation (WADA) banned the use of Xenon and argon gases; 3) the first discovery in the field of oncology that general anaesthetics used for cancer surgery can modulate the behaviour of cancer cells through hypoxia-inducible factor 1α; 4) the study of the mechanisms of neurocognitive impairment in the elderly after surgery, which elucidated for the first time the relationship between postoperative delirium and cognitive dysfunction and neuroinflammation. These achievements have provided irrefutable evidence to improve the long-term prognosis of perioperative patients and have had a profound impact on anaesthetic medicine and related clinical medical disciplines worldwide. Professor Ma has published more than 350 papers in the field of biomedicine (H index 75 and citation > 19,000) and is ranked 25,386 in the Global Scholarly Database's overall ranking of 100,000 scholars across all disciplines.
References
Yu Y, Wang L, Ni S, Li D, Liu J, Chu HY, Zhang N, Sun M, Li N, Ren Q, Zhuo Z, Zhong C, Xie D, Li Y, Zhang ZK, Zhang H, Li M, Zhang Z, Chen L, Pan X, Xia W, Zhang S, Lu A, Zhang BT, Zhang G. Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation. Nat Commun. 2022 Jul 22;13(1):4241. doi: 10.1038/s41467-022-31997-8. PMID: 35869074; PMCID: PMC9307627.
Wang L, Yu Y, Ni S, Li D, Liu J, Xie D, Chu HY, Ren Q, Zhong C, Zhang N, Li N, Sun M, Zhang ZK, Zhuo Z, Zhang H, Zhang S, Li M, Xia W, Zhang Z, Chen L, Shang P, Pan X, Lu A, Zhang BT, Zhang G. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Theranostics. 2022 Jul 18;12(13):5645-5674. doi: 10.7150/thno.63177. PMID: 35966595; PMCID: PMC9373813.
Yu S, Li D, Zhang N, Ni S, Sun M, Wang L, Xiao H, Liu D, Liu J, Yu Y, Zhang Z, Yeung STY, Zhang S, Lu A, Zhang Z, Zhang B, Zhang G. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B. 2022 May;12(5):2150-2170. doi: 10.1016/j.apsb.2022.01.012. Epub 2022 Jan 21. PMID: 35646527; PMCID: PMC9136615.