孟德尔随机化分析评估肝酶与六种特定骨骼关节相关疾病风险之间的因果关系。
Mendelian randomization to evaluate the causal relationship between liver enzymes and the risk of six specific bone and joint-related diseases.
机构信息
Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
出版信息
Front Immunol. 2023 Aug 16;14:1195553. doi: 10.3389/fimmu.2023.1195553. eCollection 2023.
BACKGROUND
Studies of liver dysfunction in relation to bone and joint-related diseases are scarce, and its causality remains unclear. Our objective was to investigate whether serum liver enzymes are causally associated with bone and joint-related diseases using Mendelian randomization (MR) designs.
METHODS
Genetic data on serum liver enzymes (alkaline phosphatase (ALP); alanine transaminase (ALT); gamma-glutamyl transferase (GGT)) and six common bone and joint-related diseases (rheumatoid arthritis (RA), osteoporosis, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and gout) were derived from independent genome-wide association studies of European ancestry. The inverse variance-weighted (IVW) method was applied for the main causal estimate. Complementary sensitivity analyses and reverse causal analyses were utilized to confirm the robustness of the results.
RESULTS
Using the IVW method, the positive causality between ALP and the risk of osteoporosis diagnosed by bone mineral density (BMD) at different sites was indicated (femoral neck, lumbar spine, and total body BMD, odds ratio (OR) [95% CI], 0.40 [0.23-0.69], 0.35 [0.19-0.67], and 0.33 [0.22-0.51], respectively). ALP was also linked to a higher risk of RA (OR [95% CI], 6.26 [1.69-23.51]). Evidence of potential harmful effects of higher levels of ALT on the risk of hip and knee OA was acquired (OR [95% CI], 2.48 [1.39-4.41] and 3.07 [1.49-6.30], respectively). No causal relationship was observed between GGT and these bone and joint-related diseases. The study also found that BMD were all negatively linked to ALP levels (OR [95% CI] for TBMD, FN-BMD, and LS-BMD: 0.993 [0.991-0.995], 0.993 [0.988-0.998], and 0.993 [0.989, 0.998], respectively) in the reverse causal analysis. The results were replicated via sensitivity analysis in the validation process.
CONCLUSIONS
Our study revealed a significant association between liver function and bone and joint-related diseases.
背景
关于肝功能与骨关节炎相关疾病的研究较少，其因果关系尚不清楚。我们的目的是使用孟德尔随机化（MR）设计来研究血清肝酶是否与骨关节炎相关疾病有因果关系。
方法
来自欧洲血统的独立全基因组关联研究中获得了血清肝酶（碱性磷酸酶（ALP）；丙氨酸转氨酶（ALT）；γ-谷氨酰转移酶（GGT））和六种常见骨关节炎相关疾病（类风湿关节炎（RA）、骨质疏松症、骨关节炎（OA）、强直性脊柱炎、银屑病关节炎和痛风）的遗传数据。应用逆方差加权（IVW）法进行主要因果估计。互补敏感性分析和反向因果分析用于确认结果的稳健性。
结果
使用 IVW 方法，发现 ALP 与不同部位骨密度（BMD）诊断的骨质疏松症风险之间存在正因果关系（股骨颈、腰椎和全身 BMD，比值比（OR）[95%置信区间]，0.40 [0.23-0.69]，0.35 [0.19-0.67]和 0.33 [0.22-0.51]）。ALP 也与 RA 的风险增加相关（OR [95%置信区间]，6.26 [1.69-23.51]）。获得了较高水平的 ALT 对髋部和膝部 OA 风险的潜在有害影响的证据（OR [95%置信区间]，2.48 [1.39-4.41]和 3.07 [1.49-6.30]）。GGT 与这些骨关节炎相关疾病之间没有因果关系。该研究还发现，BMD 均与 ALP 水平呈负相关（全身 BMD、股骨颈 BMD 和腰椎 BMD 的 OR [95%置信区间]：0.993 [0.991-0.995]、0.993 [0.988-0.998]和 0.993 [0.989，0.998]）在反向因果分析中。在验证过程中的敏感性分析中复制了这些结果。
结论
本研究揭示了肝功能与骨关节炎相关疾病之间存在显著关联。
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