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ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Bone Research
Volume 16 - 2025 |
doi: 10.3389/fendo.2025.1435295
Causal inference study of plasma proteins and blood metabolites mediating the effect of obesity-related indicators on osteoporosis
Provisionally accepted
Maomao Huang 1,2,3
Fei Xing 1,3*
Yue Hu 1 Fuhua Sun 1,3* Chi Zhang 1,2,3* Zhangyu Xv 1*
Yue Yang 1
Qi Deng 1 Ronglan Shi 1* Lei Li 1* Jiayi Zhu 1* Fangyuan Xu 1* Dan Li 1,3*
Jianxiong Wang 1,2,3*- 1 Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
- 2 Department of Rehabilitation Medicine, Southwest Medical University, Luzhou, China
- 3 Other, Luzhou, China
Background: Osteoporosis and obesity are both major global public health problems.Observational studies have found that osteoporosis might be related to obesity. Mendelian Randomization (MR) analysis could overcome the limitations of observational studies in assessing causal relationships.Objective：This study aims to evaluate the causal potential relationship between obesity-related indicators and osteoporosis by using two-sample MR analysis, and to identify potential mediators. Method: A total of 53 obesity-related indicators, 3282 plasma protein lists, and 452 blood metabolite lists were downloaded from the public data set as instrumental variables, and the osteoporosis GWAS data of the MRC IEU Open GWAS database was used as outcome indicators. Using two-sample univariate MR, multivariate MR, and intermediate MR to identify the causal relationship and mediating factors between obesity-related indicators and osteoporosis. Results: IVW model results show that 31 obesity-related indicators may have significant causal relationship with osteoporosis (P < 0.05), except for Waist circumference (id: Ieu-a-71, OR = 1.00566), the remaining 30 indicators may could reduce the risk of osteoporosis (OR 0.983-0.996). 25 plasma protein indicators may have significant causal relationship with osteoporosis (P< 0.05), and 10 of them such as ANKED46, KLRF1, and LPO, CA9 may have protective effect on osteoporosis (OR 0.996-0.999), while the other 15 such as ATP1B1, Zinc finger protein 175, may could increase the risk of osteoporosis (OR 1.001-1.004). For blood metabolite indicators, except for Alanine (id: Met a-469, OR 1.071), other six blood metabolite indicators including Uridine and 1-linoleoylglycerophosphoethanolaminecan, may have protective effect on osteoporosis (P< 0.05, OR 0.961-0.992). The direction of causal relationship of MR is all correct, the heterogeneity is all not significant and not affected by horizontal pleiotropy. Multivariate and mediated MR analysis found that the protective effect of obesity-related indicators against osteoporosis may be mediated by Histone-lysine N-methyltransferase in plasma proteins and Alanine in blood metabolites. Conclusion: Obesity may confer a protective effect against osteoporosis, potentially mediated by EHMT2 in plasma proteins and alanine in blood metabolites. Further empirical research is required to fully elucidate the mechanisms behind the influence of obesity on osteoporosis.
Keywords: obesity-related indicators, Osteoporosis, plasma proteins, Blood metabolites, mendelian analysis
Received: 20 May 2024; Accepted: 21 Jan 2025.
Copyright: © 2025 Huang, Xing, Hu, Sun, Zhang, Xv, Yang, Deng, Shi, Li, Zhu, Xu, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Fei Xing, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Fuhua Sun, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Chi Zhang, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Zhangyu Xv, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Ronglan Shi, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Lei Li, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Jiayi Zhu, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Fangyuan Xu, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Dan Li, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
Jianxiong Wang, Rehabilitation Medicine Department, The Affiliated Hospital Of Southwest Medical University, luzhou, China
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