中国组织工程研究

中国组织工程研究 ›› 2024, Vol. 28 ›› Issue (23): 3715-3721.doi: 10.12307/2024.412

• 骨组织构建 bone tissue construction • 上一篇    下一篇

类风湿性关节炎与骨质疏松症和骨密度关系的孟德尔随机化分析

武瑞骐1，2，周  毅1，夏  天1，张  驰1，杨启培1，2，张  璇2，张亚忠3，崔  伟1   

  1. 1广西中医药大学附属瑞康医院，广西壮族自治区南宁市  530000；2广西中医药大学，广西壮族自治区南宁市  530299；3梧州市中医医院骨科，广西壮族自治区梧州市  543000
  • 收稿日期:2023-05-30 接受日期:2023-07-13 出版日期:2024-08-18 发布日期:2023-09-13
  • 通讯作者: 张亚忠，副主任医师，硕士生导师，梧州市中医医院骨科，广西壮族自治区梧州市 543000 崔伟，主任医师，教授，硕士生导师，广西中医药大学附属瑞康医院，广西壮族自治区南宁市 530000
  • 作者简介:武瑞骐，男，1998年生，海南省海口市人，汉族，广西中医药大学在读硕士，主要从事脊柱和骨关节创伤性疾病防治研究。
  • 基金资助:
    国家自然科学基金资助项目(81960803)，项目参与人：张驰；广西壮族自治区临床重点专科(创伤外科)建设项目[部门预算社(2021)]，项目参与人：张驰；广西自然科学基金项目(2023GXNSFAA026075)，项目参与人：张驰；广西自然科学基金青年基金(2020GXNSFBA159053)，项目参与人：张驰；广西中医药大学校级博士研究生科研创新项目(YCBXJ2021019)，项目负责人：夏天；广西中医药大学青年创新研究团队项目(2021TD001)；广西中医药大学桂派中医药传承创新团队(2022A004)，项目参与人：夏天；广西中医药适宜技术开发与推广项目(GZSY22-39)，项目负责人：夏天；广西中医药适宜技术开发与推广项目(GZSY22-36)，项目参与人：张驰

Mendelian randomization study on the association between rheumatoid arthritis and osteoporosis and bone mineral density

Wu Ruiqi1, 2, Zhou Yi1, Xia Tian1, Zhang Chi1, Yang Qipei1, 2, Zhang Xuan2, Zhang Yazhong3, Cui Wei1   

  1. 1Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530000, Guangxi Zhuang Autonomous Region, China; 2Guangxi University of Chinese Medicine, Nanning 530299, Guangxi Zhuang Autonomous Region, China; 3Department of Orthopedics, Wuzhou Hospital of Traditional Chinese Medicine, Wuzhou 543000, Guangxi Zhuang Autonomous Region, China
  • Received:2023-05-30 Accepted:2023-07-13 Online:2024-08-18 Published:2023-09-13
  • Contact: Zhang Yazhong, Associate chief physician, Master’s supervisor, Department of Orthopedics, Wuzhou Hospital of Traditional Chinese Medicine, Wuzhou 543000, Guangxi Zhuang Autonomous Region, China Cui Wei, Chief physician, Professor, Master’s supervisor, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530000, Guangxi Zhuang Autonomous Region, China
  • About author:Wu Ruiqi, Master candidate, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530000, Guangxi Zhuang Autonomous Region, China; Guangxi University of Chinese Medicine, Nanning 530299, Guangxi Zhuang Autonomous Region, China
  • Supported by:
    the National Natural Science Foundation of China, No. 81960803 (to ZC [project participant]); Guangxi Zhuang Autonomous Region Clinical Key Specialty (Trauma Surgery) Construction Project, No. BMYSS(2021) (to ZC [project participant]); Guangxi Natural Science Foundation Project, No. 2023GXNSFAA026075 (to ZC [project participant]); Guangxi Natural Science Foundation for the Youth, No. 2020GXNSFBA159053 (to ZC [project participant]); Guangxi University of Chinese Medicine School-level Doctoral Research and Innovation Project, No. YCBXJ2021019 (to XT); Guangxi University of Chinese Medicine Youth Innovation Research Team Project, No. 2021TD001; Guangxi University of Chinese Medicine Gui School TCM Inheritance and Innovation Team, No. 2022A004 (to XT [project participant]); Guangxi Chinese Medicine Appropriate Technology Development and Promotion Project, Nos. GZSY22-39 (to XT) and GZSY22-36 (to ZC [project participant])

PDF

121

摘要：


文题释义：

孟德尔随机化：一种利用遗传变异在配子形成和受精过程中的随机分配特性来进行因果推断的人类遗传学工具，主要用于评估先前观察到的暴露与结果之间的因果关系，从而有效避免传统流行病学研究中的混淆偏倚。
骨质疏松症：一种以骨量低下、骨组织微结构损坏，导致骨脆性增加及易发生骨折为特征的全身性骨病。


背景：许多临床研究观察表明类风湿性关节炎与骨质疏松症和骨密度之间存在密切关系，但类风湿性关节炎与骨质疏松症和骨密度之间是否存在因果遗传尚不清楚。

目的：采用两样本孟德尔随机化研究方法评估类风湿性关节炎与骨质疏松症和骨密度之间潜在的因果关系，从遗传学的角度对潜在的机制提供有意义的见解，为早期预防骨质疏松症、改善疾病的发生发展提供参考。
方法：从全基因组关联研究(GWAS)公开数据库中筛选出与类风湿性关节炎相关的(P < 5×10-8)单核苷酸多态性位点作为工具变量。研究结局主要包括骨质疏松症、5个不同部位的骨密度，包括全身骨密度、腰椎骨密度、股骨颈骨密度、足跟骨密度以及前臂骨密度。逆方差加权法为该研究评估因果效应的主要分析方法，文章采用加权中位数法、简单中位数法、加权中值方法和MR-Egger回归用于补充说明，以比值比(OR)和95%可信区间(95%CI)评价类风湿性关节炎与骨质疏松症及骨密度风险之间的因果关系，使用类风湿性关节炎Cochran’s Q检验异质性，利用MR-Egger-intercept检验是否存在水平多效性。

结果与结论：①逆方差加权法结果表明遗传预测的类风湿性关节炎与骨质疏松症呈正相关(OR=1.123，95%CI：1.077-1.171，P=4.02×10-8)，异质性检验表明单核苷酸多态性位点不存在异质性(P=0.388)，MR-Egger-intercept检验未检测到水平多效性(P=0.571)，敏感性分析显示研究结果没有产生偏倚。②类风湿性关节炎与5个部位的骨密度之间不存在因果关系显示如下：全身骨密度(OR=1.000，95%CI：0.988-1.012，P=0.925)、腰椎骨密度(OR=0.999，95%CI：0.982-1.016，P=0.937)、股骨颈骨密度(OR=1.001，95%CI：0.986-1.016，P=0.866)、足跟骨密度(OR=0.996，95%CI：0.989-1.004，P=0.419)、前臂骨密度(OR=1.063，95%CI：0.970-1.031，P=0.996)。MR-Egger-intercept分析未检测到潜在的水平多效性(全身骨密度：P=0.253；腰椎骨密度：P=0.638；股骨颈骨密度：P=0.553；足跟骨密度：P=0.444；前臂骨密度：P=0.079)。③类风湿性关节炎可能通过慢性炎症与骨的形成、骨溶解和吸收之间的相互作用导致骨质疏松症，此外，糖皮质激素的使用和类风湿性关节炎患者身体内的自身抗体(如抗瓜氨酸蛋白抗体)阳性也与骨质疏松症存在相关性。④未来研究需重点关注类风湿性关节炎患者全身免疫水平的系统性炎症指标、糖皮质激素的规范使用以及定期进行骨质疏松症风险筛查。

https://orcid.org/0000-0003-2729-307X(武瑞骐)；https://orcid.org/0009-0006-0412-0976(张亚忠)；https://orcid.org/0000-0003-2011-7508(崔伟)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 骨质疏松症, 类风湿性关节炎, 骨密度, 孟德尔随机化, 单核苷酸多态性, 因果关联, 全基因组关联研究, 工具变量

Abstract: BACKGROUND: Many clinical research observations have indicated a close association between rheumatoid arthritis and osteoporosis as well as bone mineral density (BMD). However, it remains unclear whether there is a causal genetic relationship between rheumatoid arthritis and the development of osteoporosis and alterations of BMD.
OBJECTIVE: To assess the potential causal relationship between rheumatoid arthritis and osteoporosis as well as BMD using a two-sample Mendelian randomization approach, provide meaningful insights from a genetic perspective into the underlying mechanisms and offer a reference for early prevention of osteoporosis and improvement in the progression of the disease.
METHODS: We conducted a study using data from publicly available genome-wide association studies databases to identify single nucleotide polymorphisms associated with rheumatoid arthritis as instrumental variables (P < 5×10-8). The main outcomes of the study included osteoporosis and BMD at five different sites, including total body BMD, lumbar spine BMD, femoral neck BMD, heel BMD, and forearm BMD. The inverse variance-weighted method was used as the primary analysis method to evaluate causal effects. Weighted median, simple median, weighted mode and MR-Egger regression were used as supplementary analyses. Causal relationships between rheumatoid arthritis and the risk of osteoporosis and BMD were assessed using odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q test and horizontal pleiotropy was evaluated using MR-Egger intercept tests.
RESULTS AND CONCLUSION: The inverse variance-weighted analysis demonstrated a positive association between genetically predicted rheumatoid arthritis and osteoporosis (OR=1.123, 95% CI: 1.077-1.171; P=4.02×10-8). Heterogeneity test (P=0.388) indicated no significant heterogeneity among the single nucleotide polymorphisms. MR-Egger intercept (P=0.571) tests did not detect horizontal pleiotropy, and sensitivity analysis showed no evidence of bias in the study results. There was no causal relationship between rheumatoid arthritis and BMD at the five different sites. The total body BMD (OR=1.000, 95% CI: 0.988-1.012; P=0.925), lumbar spine BMD (OR=0.999, 95% CI: 0.982-1.016; P=0.937), femoral neck BMD (OR=1.001, 95% CI: 0.986-1.016; P=0.866), heel BMD (OR=0.996, 95% CI: 0.989-1.004; P=0.419), and forearm BMD (OR=1.063, 95% CI: 0.970-1.031; P=0.996) indicated no significant association. MR-Egger intercept analysis did not detect potential horizontal pleiotropy (total body BMD: P=0.253; lumbar spine BMD: P=0.638; femoral neck BMD: P=0.553; heel BMD: P=0.444; forearm BMD: P=0.079). Rheumatoid arthritis may contribute to the development of osteoporosis through the interaction between chronic inflammation and bone formation, resorption, and absorption. Additionally, the use of glucocorticoids and the presence of autoantibodies (such as anti-citrullinated protein antibody) in patients with rheumatoid arthritis showed associations with osteoporosis. Future research should focus on monitoring systemic inflammatory markers, standardized use of glucocorticoids, and regular screening for osteoporosis risk in patients with rheumatoid arthritis.

Key words: osteoporosis, rheumatoid arthritis, bone mineral density, Mendelian randomization, single nucleotide polymorphism, causal association, genome-wide association study, instrumental variable

中图分类号: