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The Impact of Non-alcohol Fatty Liver Disease on Bone Mineral Density is Mediated by Sclerostin by Mendelian Randomization Study

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Abstract

Non-alcoholic fatty liver disease (NAFLD) has been found to be associated with osteoporosis (OP) in observational studies. However, the precise causal relationship between NAFLD and OP remains unclear. Here, we used Mendelian randomization (MR) to explore the causal relationship. We selected NAFLD-related single-nucleotide polymorphisms from a genome-wide meta-analysis (8434 cases and 434,770 controls) as instrumental variants. We used inverse variance weighted analysis for the primary MR analysis. Furthermore, we used similar methodologies in parallel investigations of other chronic liver diseases (CLDs). We performed sensitivity analyses to ensure the reliability of the results. We observed a causality between NAFLD and forearm bone mineral density (FABMD) (beta-estimate [β]: − 0.212; p-value: 0.034). We also found that sclerostin can act as a mediator to influence the NAFLD and FABMD pathways to form a mediated MR network (mediated proportion = 8.8%). We also identified indications of causal relationships between other CLDs and OP. However, we were unable to establish any associated mediators. Notably, our analyses did not yield any evidence of pleiotropy. Our findings have implications in the development of preventive and interventional measures aimed at managing low bone mineral density in patients with NAFLD.

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Data Availability

All genome-wide association studies can be accessed via the Open GWAS database (https://gwas.mrcieu.ac.uk/ and https://www.ebi.ac.uk/gwas/). The summary statistics of GWAS meta-analyses generated in this study can be accessible upon request.

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Acknowledgements

We extend our gratitude to the participants and investigators involved in the UK Biobank, FinnGen, GEFOS, eMERGE, NHSBT, KORA, YFS, and MAGIC research projects. In addition, we express appreciation towards all the other investigators for their efforts in providing accessible summary statistics.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Gastroenterology, Xiangya Hospital, Central South University, No.88 Xiangya Road, Kaifu District, Changsha, 410000, Hunan Province, China

    Yuan Liu, Longjiao Cai & Aimin Leng

  2. Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China

    Mengqin Yuan

  3. Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Jian He

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Contributions

Conceptualization: Liu Y, Leng AM proposed the idea and designed the study; Data curation: Liu Yuan, and Cai LJ managed the data; Formal analysis: Liu Yuan, Meng QY, and He J analyzed the data; Funding acquisition: Leng AM acquire the funding; Investigation: Liu Yuan, Meng QY, and He J performed the research and collected data; Methodology: Liu Yuan and He J provided methodology; Project administration: Leng AM administrated the project; Resources: Liu Yuan, Meng QY, and He J coordinated the resources; Software: Liu Yuan, Meng QY, and He J developed the algorithm; Supervision: Leng AM supervised the study; Roles/Writing - original draft: Liu Y; Writing—review & editing: Leng AM.

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Correspondence to Aimin Leng.

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Yuan Liu, Mengqin Yuan, Jian He, Longjiao Cai, and Aimin Leng declare that they have no conflict of interest. The authors have no financial or proprietary interests in any material discussed in this article. The authors have no personal, financial, or institutional interest and ethical/legal conflicts involved in this article.

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Liu, Y., Yuan, M., He, J. et al. The Impact of Non-alcohol Fatty Liver Disease on Bone Mineral Density is Mediated by Sclerostin by Mendelian Randomization Study. Calcif Tissue Int 114, 502–512 (2024). https://doi.org/10.1007/s00223-024-01204-5

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