两样本孟德尔随机化分析评估炎症性肠病和骨质疏松症之间的因果关联。
Two-sample Mendelian randomization analysis evaluates causal associations between inflammatory bowel disease and osteoporosis.
机构信息
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Colorectal Cancer Research Center, Shanghai, China.
出版信息
Front Public Health. 2023 May 26;11:1151837. doi: 10.3389/fpubh.2023.1151837. eCollection 2023.
INTRODUCTION
Over the past few years, multiple observational studies have speculated a potential association between inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), and osteoporosis. However, no consensus has been reached regarding their interdependence and pathogenesis. Herein, we sought to further explore the causal associations between them.
METHODS
We validated the association between IBD and reduced bone mineral density in humans based on genome-wide association studies (GWAS) data. To investigate the causal relationship between IBD and osteoporosis, we performed a two-sample Mendelian randomization study using training and validation sets. Genetic variation data for IBD, CD, UC, and osteoporosis were derived from published genome-wide association studies in individuals of European ancestry. After a series of robust quality control steps, we included eligible instrumental variables (SNPs) significantly associated with exposure (IBD/CD/UC). We adopted five algorithms, including MR Egger, Weighted median, Inverse variance weighted, Simple mode, and Weighted mode, to infer the causal association between IBD and osteoporosis. In addition, we evaluated the robustness of Mendelian randomization analysis by heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate Mendelian randomization.
RESULTS
Genetically predicted CD was positively associated with osteoporosis risk, with ORs of 1.060 (95% CIs 1.016, 1.106; = 0.007) and 1.044 (95% CIs 1.002, 1.088; = 0.039) for CD in the training and validation sets, respectively. However, Mendelian randomization analysis did not reveal a significant causal relationship between UC and osteoporosis ( > 0.05). Furthermore, we found that overall IBD was associated with osteoporosis prediction, with ORs of 1.050 (95% CIs 0.999, 1.103; = 0.055) and 1.063 (95% CIs 1.019, 1.109; = 0.005) in the training and validation sets, respectively.
CONCLUSION
We demonstrated the causal association between CD and osteoporosis, complementing the framework for genetic variants that predispose to autoimmune disease.
简介
在过去的几年中，多项观察性研究推测炎症性肠病（IBD）——包括溃疡性结肠炎（UC）和克罗恩病（CD）——与骨质疏松症之间存在潜在关联。然而，它们之间的相互依存关系和发病机制尚未达成共识。在此，我们试图进一步探讨它们之间的因果关系。
方法
我们基于全基因组关联研究（GWAS）数据验证了 IBD 与骨密度降低之间的关联。为了研究 IBD 和骨质疏松症之间的因果关系，我们使用训练集和验证集进行了两样本孟德尔随机化研究。IBD、CD、UC 和骨质疏松症的遗传变异数据源自欧洲裔个体的已发表全基因组关联研究。在进行了一系列严格的质量控制步骤后，我们纳入了与暴露（IBD/CD/UC）显著相关的合格工具变量（SNP）。我们采用了五种算法，包括 MR Egger、加权中位数、逆方差加权、简单模式和加权模式，来推断 IBD 和骨质疏松症之间的因果关系。此外，我们通过异质性检验、多效性检验、单变量孟德尔随机化检验和多变量孟德尔随机化检验来评估孟德尔随机化分析的稳健性。
结果
遗传预测的 CD 与骨质疏松症风险呈正相关，在训练集和验证集中，CD 的 OR 分别为 1.060（95%CI 1.016, 1.106；=0.007）和 1.044（95%CI 1.002, 1.088；=0.039）。然而，孟德尔随机化分析并未显示 UC 与骨质疏松症之间存在显著的因果关系（>0.05）。此外，我们发现总体 IBD 与骨质疏松症预测相关，在训练集和验证集中，OR 分别为 1.050（95%CI 0.999, 1.103；=0.055）和 1.063（95%CI 1.019, 1.109；=0.005）。
结论
我们证明了 CD 与骨质疏松症之间存在因果关系，这补充了易患自身免疫性疾病的遗传变异框架。
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