Department of Gastroenterology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China.
Department of Anesthesiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China.
Front Immunol. 2024 Oct 9;15:1453657. doi: 10.3389/fimmu.2024.1453657. eCollection 2024.
Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns.
We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using two-step mediation analyses.
The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, =0.001), total body bone mineral density (β: -0.025, =0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, =0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, =0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, =0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis.
The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18.
大量观察性数据表明乳糜泻（CeD）与骨质疏松症之间存在关联，但因果关系和介导机制仍未确定。在此，我们进行了一项孟德尔随机化（MR）研究来解决这些问题。
我们从包含 4533 例病例和 10750 例对照的欧洲裔人群的大型全基因组关联研究（GWAS）中获得了 CeD 的汇总统计数据。骨质疏松症相关特征和炎症细胞因子的 GWAS 数据来自英国生物库、芬兰基因、IEU OpenGWAS 数据库或 GWAS 目录。采用两样本 MR 反方差加权法评估 CeD 与骨质疏松症相关特征之间的遗传关联。使用两步中介分析探讨 CeD 向骨质疏松症的潜在炎症介导因子。
主要的 MR 分析表明，遗传预测的 CeD 与骨质疏松症（比值比 [OR]：1.110，95%置信区间 [CI]：1.043-1.182，=0.001）、全身骨矿物质密度（β：-0.025，=0.039）和骨质疏松性骨折（OR：1.124，95%CI：1.009-1.253，=0.034）之间存在因果关系。广泛的敏感性分析证实了这些发现。在候选炎症细胞因子中，只有白细胞介素-18 被观察到介导 CeD 对骨质疏松症的影响，间接 OR 为 1.020（95%CI：1.000-1.040，=0.048）和中介比例为 18.9%。白细胞介素-18 的中介作用可以在其他数据集（OR：1.015，95%CI：1.001-1.029，=0.041）中得到验证。贝叶斯共定位分析支持白细胞介素-18 在骨质疏松症中的作用。
本 MR 研究表明 CeD 与骨质疏松症风险增加相关，这可能部分是由白细胞介素-18 的上调介导的。
