The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyua People's Hospital), Qingyuan, China.
Department of Medical Imaging, The Second Clinical School of Guangzhou Medical University, Guangzhou, China.
PLoS One. 2023 Oct 19;18(10):e0292881. doi: 10.1371/journal.pone.0292881. eCollection 2023.
BACKGROUND: Reduced bone mineral density (BMD) and osteoporosis are common in chronic liver diseases. However, the causal effect of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) on BMD remains uncertain. OBJECTIVES: This study uses a two-sample Mendelian randomization (MR) design to evaluate the genetically predicted effect of ALD and NAFLD on BMDs using summary data from publically available genome-wide association studies (GWASs). METHODS: The GWAS summary statistics of ALD (1416 cases and 213,592 controls) and NAFLD (894 cases and 217,898 controls) were obtained from the FinnGen consortium. BMDs of four sites (total body, n = 56,284; femoral neck, n = 32,735; lumbar spine, n = 28,498; forearm, n = 8143) were from the GEnetic Factors for OSteoporosis Consortium. Data for alcohol consumption (n = 112,117) and smoking (n = 33,299) and serum 25-Hydroxyvitamin D (25-OHD) level (n = 417,580) were from UK-biobank. We first performed univariate MR analysis with the Inverse Variance Weighted (IVW) method as the primary analysis to investigate the genetically predicted effect of ALD or NAFLD on BMD. Then, multivariate MR and mediation analysis were performed to identify whether the effect was mediated by alcohol consumption, smoking, or serum 25-OHD level. RESULTS: The MR results suggested a robust genetically predicted effect of ALD on reduced BMD in the femoral neck (FN-BMD) (IVW beta = -0.0288; 95% CI: -0.0488, -0.00871; P = 0.00494) but not the other three sites. Serum 25-OHD level exhibited a significant mediating effect on the association between ALD and reduced FN-BMD albeit the proportion of mediation was mild (2.21%). No significant effects of NAFLD, alcohol consumption, or smoking on BMD in four sites, or reverse effect of BMD on ALD or NAFLD were detected. CONCLUSION: Our findings confirm the genetically predicted effect of ALD on reduced FN-BMD, and highlight the importance of periodic BMD and serum 25-OHD monitoring and vitamin D supplementation as needed in patients with ALD. Future research is required to validate our results and investigate the probable underlying mechanisms.
背景：慢性肝病患者常出现骨密度降低（BMD）和骨质疏松症。然而，酒精性肝病（ALD）和非酒精性脂肪性肝病（NAFLD）对 BMD 的因果影响仍不确定。
目的：本研究使用两样本 Mendelian 随机化（MR）设计，利用公开可得的全基因组关联研究（GWAS）汇总数据，评估 ALD 和 NAFLD 对 BMD 的遗传预测效应。
方法：从 FinnGen 联盟获得 ALD（1416 例和 213592 例对照）和 NAFLD（894 例和 217898 例对照）GWAS 汇总统计数据。BMD 的四个部位（全身，n=56284；股骨颈，n=32735；腰椎，n=28498；前臂，n=8143）来自遗传因素骨质疏松症联盟。酒精摄入量（n=112117）和吸烟（n=33299）以及血清 25-羟维生素 D（25-OHD）水平（n=417580）的数据来自 UK-biobank。我们首先使用逆方差加权（IVW）方法进行单变量 MR 分析，作为主要分析方法，以研究 ALD 或 NAFLD 对 BMD 的遗传预测作用。然后，进行多变量 MR 和中介分析，以确定该作用是否由酒精摄入量、吸烟或血清 25-OHD 水平介导。
结果：MR 结果表明，ALD 对股骨颈（FN-BMD）的 BMD 降低具有稳健的遗传预测作用（IVW 贝塔=-0.0288；95%CI：-0.0488，-0.00871；P=0.00494），但对其他三个部位没有影响。血清 25-OHD 水平对 ALD 与 FN-BMD 降低之间的关联具有显著的中介作用，尽管中介作用的比例较小（2.21%）。未发现 NAFLD、酒精摄入量或吸烟对四个部位的 BMD 有显著影响，也未发现 BMD 对 ALD 或 NAFLD 的反向影响。
结论：我们的研究结果证实了 ALD 对 FN-BMD 降低的遗传预测作用，并强调了在 ALD 患者中定期进行 BMD 和血清 25-OHD 监测以及按需补充维生素 D 的重要性。需要进一步的研究来验证我们的结果并探讨可能的潜在机制。
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