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Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis

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Abstract

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016–1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023–1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025–1.067; P = 8.17 × 10−6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.

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Data Availability

See Table S1.

Abbreviations

BMI:

Body mass index

BAT:

Bioavailable testosterone

CAUSE:

Causal analysis using summary effect estimates

CI:

Confidence interval

GWAS:

Genome-wide association study

IV:

Instrumental variable

IVW:

Inverse variance weighted

LDSC:

Linkage disequilibrium score regression

MR:

Mendelian randomization

MVMR:

Multivariable Mendelian randomization

OR:

Odds ratio

PBC:

Primary biliary cholangitis

PRESSO:

Pleiotropy residual sum and outlier

SHBG:

Sex hormone binding globulin

SNP:

Single nucleotide polymorphism

TT:

Total testosterone

TG:

Triglycerides

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Acknowledgements

The authors thank all of the investigators participants for sharing genetic association estimates for PBC and osteoporosis. We acknowledge the use of Biorender to create graphic abstract and Fig. 1.

Funding

This study was funded by the National Natural Science Foundation of China grants (#82270554 and 81922010 to RT; #81830016 and 82130017 to XM) and Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 20XD1422500 to RT). The funding source was not involved in study design, analysis, and interpretation of the data.

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Author notes

  1. Yi Wu and Qiwei Qian contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China

    Yi Wu, Qiwei Qian, Qiaoyan Liu, Rui Wang, Xiting Pu, Yao Li, Huayang Zhang, Zhengrui You, Qi Miao, Xiao Xiao, Min Lian, Qixia Wang, Xiong Ma & Ruqi Tang

  2. Department of Hepatology, Clinical Research Center, Nagasaki University Graduate School of Biomedical Sciences, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura City, Nagasaki, 856-8562, Japan

    Minoru Nakamura

  3. Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA

    M. Eric Gershwin

  4. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China

    Zhiqiang Li

  5. Qingdao University, Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao, China

    Zhiqiang Li

  6. Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiong Ma

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  1. Yi Wu
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Contributions

Dr. Tang and Dr. Ma had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Ruqi Tang, Xiong Ma, Zhiqiang Li, and M. Eric Gershwin. Acquisition, analysis, or interpretation of data: Yi Wu, Qiwei Qian, Minoru Nakamura, Qiaoyan Liu, Rui Wang, Xiting Pu, Yao Li, and Huayang Zhang. Drafting of the manuscript: Yi Wu and Qiwei Qian. Critical review of the manuscript for important intellectual content: Ruqi Tang, Xiong Ma, Zhiqiang Li, and M. Eric Gershwin. Statistical analysis: Yi Wu, Qiwei Qian, and Zhiqiang Li. Obtained funding: Xiong Ma and Ruqi Tang. Administrative, technical, or material support: Zhengrui You, Qi Miao, Xiao Xiao, Min Lian, and Qixia Wang. Supervision: Ruqi Tang and Xiong Ma.

Corresponding authors

Correspondence to Zhiqiang Li, Xiong Ma or Ruqi Tang.

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Wu, Y., Qian, Q., Liu, Q. et al. Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis. Clinic Rev Allerg Immunol (2024). https://doi.org/10.1007/s12016-024-08986-4

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