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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 [article]

Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till Andlauer, Michelle Yau, April Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe (+25 others)
2022 medRxiv   pre-print

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https://web.archive.org/web/20220619010607/https://www.medrxiv.org/content/medrxiv/early/2022/06/16/2022.06.13.22275915.full.pdf

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Sclerostin inhibition is a new therapeutic approach for increasing bone mineral density (BMD) but its cardiovascular safety is unclear. We conducted a genome-wide association study (GWAS) meta-analysis of circulating sclerostin in 33,961 Europeans followed by Mendelian randomization (MR) to estimate the causal effects of sclerostin on 15 atherosclerosis-related diseases and risk factors. GWAS meta-analysis identified 18 variants independently associated with sclerostin, which including a novel
more » ... is signal in the SOST region and three trans signals in B4GALNT3, RIN3 and SERPINA1 regions that were associated with opposite effects on circulating sclerostin and eBMD. MR combining these four SNPs suggested lower sclerostin increased hypertension risk (odds ratio [OR]=1.09, 95%CI=1.04 to 1.15), whereas bi-directional analyses revealed little evidence for an effect of genetic liability to hypertension on sclerostin levels. MR restricted to cis (SOST) SNPs additionally suggested sclerostin inhibition increased risk of type 2 diabetes (T2DM) (OR=1.26; 95%CI=1.08 to 1.48) and myocardial infarction (MI) (OR=1.31, 95% CI=1.183 to 1.45). Furthermore, these analyses suggested sclerostin inhibition increased coronary artery calcification (CAC) (beta=0.74, 95%CI=0.33 to 1.15), levels of apoB (beta=0.07; 95%CI=0.04 to 0.10; this result was driven by rs4793023) and triglycerides (beta=0.18; 95%CI=0.13 to 0.24), and reduced HDL-C (beta=-0.14; 95%CI=-0.17 to -0.10). This study provides genetic evidence to support a causal effect of sclerostin inhibition on increased hypertension risk. Cis-only analyses suggested that sclerostin inhibition additionally increases the risk of T2DM, MI, CAC, and an atherogenic lipid profile. Together, our findings reinforce the requirement for strategies to mitigate against adverse effects of sclerostin inhibitors like romosozumab on atherosclerosis and its related risk factors.
doi:10.1101/2022.06.13.22275915 fatcat:dryjzx57zrgtrorqp2aonqxiye
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Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till Andlauer, Michelle Yau, April Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatel, Kaare M Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia Peyser, Maryam Kavousi, Paul S De Vries, Clint Miller, Maxime Bos, Sander 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. "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." medRxiv (2022)