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The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization

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Abstract

This study aimed to examine the association between sex hormone-binding globulin (SHBG) and osteoporosis through a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR). We used the National Health and Nutrition Examination Survey (NHANES) 2013–2014 and 2015–2016 data, with exposure as serum SHBG and outcome as osteoporosis and performed multivariate logistic regression to test the correlation between SHBG and osteoporosis. To determine the causal relationship between SHBG and osteoporosis, a two-sample bidirectional MR was employed. The genome-wide association study (GWAS) dataset for SHBG (n = 189,473) was obtained from the IEU database, and the GWAS dataset for osteoporosis (n = 212,778) was obtained from the FinnGen bioBank. The principal MR technique was inverse-variance weighting (IVW). In MR analyses, the MR-Egger intercept and Cochran Q test were used to detect multiple validity and horizontal heterogeneity. 1249 older adult participants (age ≥ 60) were involved in the cross-sectional study, including 113 osteoporosis cases. We identified a significant relationship between circulating SHBG concentration and osteoporosis risk [OR 3.963, 95% CI (2.095–7.495), P < 0.05]. Subgroup analysis indicated that SHBG was closely linked to the risk of osteoporosis in the female population [OR 1.008, 95% CI (1.002–1.013), P = 0.005] but not in males (P = 0.065). In addition, The IVW approach suggested a causal connection between SHBG and increased osteoporosis risk [OR 1.479, 95% CI (1.144–1.912), P = 0.003], and the MR-Egger intercept and the Cochran Q test validated the consistency of the MR results. Finally, the reverse MR analysis declined to identify a causal relation between SHBG and osteoporosis. Our research demonstrates a significant causal connection between circulating SHBG levels and increased osteoporosis risk. These results indicate that high SHBG may be associated with the risk of osteoporosis in postmenopausal women, but more research is needed.

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Data Availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We want to express our gratitude to the volunteers and investigators involved in the FinnGen bioBank, NHANES, and IEU GWAS project for their contributions to this human medical research.

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Author notes

  1. Wei Huang and Yingqi Xiao have representing equal contributions.

Authors and Affiliations

  1. Department of Orthopaedics, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, No. 120 Guidan Road, Nanhai District, Foshan, 528000, Guangdong, China

    Wei Huang & Hu Liu

  2. Department of Pulmonary and Critical Care Medicine, Dongguan Tungwah Hospital, Dongguan, China

    Yingqi Xiao & Li Zhang

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  1. Wei Huang
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  4. Hu Liu
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Contributions

WH carried out the acquisition and interpretation of data and was the major contributor to drafting the manuscript. YX carried out the partial data collection and analysis, has made equal contributions as WH, LZ participated in drawing tables and diagrams. HL is responsible for correcting the language and grammar, contributed to the ideas of the article and reviewed/revised the manuscript. All authors provided final approval for publishing the manuscript.

Corresponding author

Correspondence to Hu Liu.

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Conflict of interest

Wei Huang, Hu Liu, Li Zhang, and Yingqi Xiao announced that there is no conflict of interest between them.

Ethical Approval and Consent to Participate

Given that the data for this study were obtained from open access IEU project, FinnGen bioBank, and NHANES database, no additional clinical trial registration or ethical approval was required.

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All authors agree to this submission.

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Supplementary Information

Below is the link to the electronic supplementary material.

223_2023_1166_MOESM1_ESM.png

Supplementary file1 (PNG 2930 KB)— Forest diagram of a causal relationship between SHBG and osteoporosis based on the IVW method. IVW: Inverse-variance weighting

Supplementary file2 (PNG 2873 KB)— The “leave-one-out” diagram of the causal relationship between SHBG and osteoporosis

223_2023_1166_MOESM3_ESM.png

Supplementary file3 (PNG 255 KB)— Forest diagram of reverse MR analyse between SHBG and osteoporosis based on IVW method

223_2023_1166_MOESM4_ESM.xlsx

Supplementary file4 (XLSX 24 KB)— Characteristics of the genetic instrument variables for the SHGB at the genome-wide significance level (P < 5 × 10–8)

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Huang, W., Xiao, Y., Zhang, L. et al. The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization. Calcif Tissue Int 114, 237–245 (2024). https://doi.org/10.1007/s00223-023-01166-0

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  • DOI: https://doi.org/10.1007/s00223-023-01166-0

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