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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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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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.
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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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DOI: https://doi.org/10.1007/s12016-024-08986-4