2型糖尿病与踝关节骨折风险的两样本孟德尔随机化研究

孟思宇; 陈秀民

doi:10.16766/j.cnki.issn.1674-4152.004433

2型糖尿病与踝关节骨折风险的两样本孟德尔随机化研究

doi: 10.16766/j.cnki.issn.1674-4152.004433

孟思宇¹,
陈秀民^2, ,

1.
河南中医药大学骨伤学院, 河南郑州 450046
2.
河南中医药大学附属濮阳市中医医院骨二科, 河南濮阳 457003

基金项目:

河南省中医药科学研究专项课题项目 2022ZY1192

河南省中医药科学研究专项课题项目 2024ZY2193

详细信息

通讯作者:
陈秀民，E-mail：CXm4427744@163.com

中图分类号: R587.1 R684
计量
- 文章访问数: 17
- HTML全文浏览量: 6
- PDF下载量: 1
- 被引次数: 0
出版历程
- 收稿日期: 2025-02-11
- 网络出版日期: 2026-06-02

A two-sample Mendelian randomized study of type 2 diabetes versus ankle fracture risk

MENG Siyu¹,
CHEN Xiumin^{2
, ,}

1.
College of Orthopedics and Traumatology, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan 450046, China

摘要

摘要: 目的研究表明糖尿病在关节骨折的发生、发展中起着重要的作用。本研究采用两样本孟德尔随机化分析探讨糖尿病与踝关节骨折的因果关系。方法收集已发表的全基因组关联研究(GWAS)的数据，通过剔除连锁不平衡以及混杂因素，设置相关阈值，筛选出116个单核苷酸多态性(SNPs)，作为研究的变量工具(IVs)。以糖尿病相关位点为工具变量，采用逆方差加权(IVW)、MR-Egger、加权中位数(WME)、简单多变量分析(SM)和加权多变量分析(WM)评估糖尿病与踝关节骨折风险的关联。利用留一法进行敏感性分析，采用敏感性分析评价结果的稳健性，并通过可视化手段进一步评估MR分析结果的可靠性与稳健性，采用Cochran' s Q检验检测工具变量间的异质性。结果统计学分析显示糖尿病与踝关节骨折存在显著的因果关系(IVW：OR=1.001，95% CI=1.001~1.002，P=0.035)。MR分析结果显示，MR Egger(P=0.007)、加权中位数法(P=0.006)、加权模式法(P=0.002)的分析结果进一步验证了这一发现，以上方法得到的因果关系方向一致，留一法分析未发现显著影响整体结果的单个SNP，异质性检验以及多效性实验结果均佐证了MR结论的可靠性与稳健性。结论糖尿病与踝关节骨折存在正向因果关系，糖尿病与踝关节骨折风险增加相关。
- 糖尿病 /
- 踝关节 /
- 骨折 /
- 因果关系
Abstract: Objective It has been proven that diabetes mellitus plays an important role in the occurrence and development of joint fractures. In this study, a two-sample Mendelian randomization analysis was conducted to investigate the causal relationship between diabetes and ankle fractures. Methods Data from published genome-wide association studies (GWAS) were collected, and 116 single-nucleotide polymorphisms (SNPs) were selected as instrumental variable (IVs) by removing linkage disequilibrium and confounding factors, setting correlation thresholds. The association between diabetes mellitus and the risk of ankle fracture was evaluated by inverse variance-weighted (IVW), MR-Egger, weighted median (WME), simple multivariate analysis (SM), and weighted multivariate analysis (WM). The sensitivity analysis was carried out by using the leave-one-out method, and the robustness of the results was evaluated by sensitivity analysis. The reliability and robustness of the MR analysis results were further evaluated by visual means. Cochran's Q test was used to detect heterogeneity between instrument variables. Results Statistical analysis showed that there was a significant causal relationship between diabetes mellitus and ankle fracture (IVW: OR=1.001, 95% CI: 1.001-1.002, P=0.035). The results of MR analysis showed that MR Egger (P=0.007), weighted median method (P=0.006), the results of the weighted model method (P=0.002) further verified this finding, the causal relationship obtained by the above methods was in the same direction, and the analysis of the leave-one-out method did not find a single SNP that significantly affected the overall results, and the heterogeneity test and pleiotropic experimental results supported the reliability and robustness of the MR conclusions. Conclusion There is a positive causal relationship between diabetes and ankle fractures, and diabetes is associated with an increased risk of ankle fractures.
- Diabetes mellitus /
- Ankle joint /
- Fractures /
- Causal relationship

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图 1 两样本MR分析结果散点图

Figure 1. Scatter plot of two-sample MR analysis results

下载: 全尺寸图片幻灯片

表 1 两样本MR研究GWAS数据信息

Table 1. Information on GWAS data for two-sample Mendelian randomization studies

变量	样本量(例)	病例组(例)	对照组(例)	样本来源地	文献发表年份	网址
2型糖尿病	655 666	61 714	1 178	欧洲	2018	https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST006867/
踝关节骨折	460 340	6 479	453 861	欧洲	2018	https://gwas.mrcieu.ac.uk/datasets/ukb-b-15582/

下载: 导出CSV

表 2 T2DM和踝关节骨折关系的MR分析结果

Table 2. MR analysis results of the association between T2DM and ankle fractures

方法	OR值	95% CI	P值
MR Egger	1.003	1.001~1.004	0.007
WME	1.002	1.000~1.003	0.006
IVW	1.001	1.001~1.002	0.035
Simple mode	1.001	0.998~1.004	0.392
Weighted mode	1.002	1.001~1.004	0.002

下载: 导出CSV

参考文献(22)

[1]	CARTER T H, OLIVER W M, BELL K R, et al. Operative vs nonoperative management of unstable medial malleolus fractures: a randomized clinical trial[J]. JAMA Netw Open, 2024, 7(1): e2351308. DOI: 10.1001/jamanetworkopen.2023.51308.
[2]	焦璇, 刘艳红, 李玲. 动态血糖监测联合胰岛素泵对2型糖尿病合并手外伤病人术后转归影响[J]. 青岛大学学报(医学版), 2024, 60(3): 433-435. JIAO X, LIU Y H, LI L. Effect of dynamic blood glucose monitoring combined with insulin pump on the postoperative outcome of patients with type 2 diabetes and hand injury[J]. Journal of Qingdao University(Medical Sciences), 2024, 60(3): 433-435.
[3]	PIGEYRE M, GERSTEIN H, AHLQVIST E, et al. Identifying blood biomarkers for type 2 diabetes subtyping: a report from the ORIGIN trial[J]. Diabetologia, 2023, 66(6): 1045-1051. doi: 10.1007/s00125-023-05887-7
[4]	刘瑜婷, 石敏, 陈燕娜, 等. 血清C1q/肿瘤坏死因子相关蛋白9水平与妊娠期糖尿病及其胰岛素抵抗的关系[J]. 中华全科医学, 2024, 22(2): 195-197, 229. doi: 10.16766/j.cnki.issn.1674-4152.003363 LIU Y T, SHI M, CHEN Y N, et al. Serum levels of C1q/TNF-related protein 9 and its association with insulin resistance in gestational diabetes mellitus[J]. Chinese Journal of General Practice, 2024, 22(2): 195-197, 229. doi: 10.16766/j.cnki.issn.1674-4152.003363
[5]	谢艳华, 邱明俊, 张云. 分阶段个体化护理管理对老年糖尿病患者踝关节骨折术后治疗效果的影响[J]. 当代护士(下旬刊), 2023, 30(2): 84-87. XIE Y H, QIU M J, ZHANG Y. To explore the effect of staged and individualized nursing management on postoperative treatment of ankle fracture in elderly diabetic patients[J]. Modern Nurse, 2023, 30(2): 84-87.
[6]	高鹏, 邵晋康. 2型糖尿病骨折风险评价的研究进展[J]. 中国实用内科杂志, 2023, 43(5): 424-429. GAO P, SHAO J K. Research progress of fracture risk assessment in type 2 diabetes mellitus[J]. Chinese Journal of Practical Internal Medicine, 2023, 43(5): 424-429.
[7]	张俏, 周学志, 陈炳合, 等. 2型糖尿病与结直肠癌发生风险的两样本孟德尔随机化研究[J]. 中华全科医学, 2024, 22(9): 1471-1474, 1570. doi: 10.16766/j.cnki.issn.1674-4152.003661 ZHANG Q, ZHOU X Z, CHEN B H, et al. A two sample Mendelian randomization study of type 2 diabetes mellitus and colorectal cancer risk[J]. Chinese Journal of General Practice, 2024, 22(9): 1471-1474, 1570. doi: 10.16766/j.cnki.issn.1674-4152.003661
[8]	XING X, WANG Y N, PAN F M, et al. Osteoarthritis and risk of type 2 diabetes: a two-sample Mendelian randomization analysis[J]. Diabetes, 2023, 15(11): 987-993. doi: 10.1111/1753-0407.13451
[9]	HO J, MAK C C H, SHARMA V, et al. Mendelian randomization studies of lifestyle-related risk factors for osteoarthritis: a PRISMA review and meta-analysis[J]. Int J Mol Sci, 2022, 23(19): 11906. DOI: 10.3390/ijms231911906.
[10]	CARTER A R, SANDERSON E, HAMMERTON G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation[J]. Eur J Epidemiol, 2021, 36(5): 465-478. doi: 10.1007/s10654-021-00757-1
[11]	CHEN L L, YANG H Q, LI H T, et al. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study[J]. Hepatology, 2022, 75(4): 785-796. doi: 10.1002/hep.32183
[12]	LIN Z T, PAN I, PAN W. A practical problem with Egger regression in Mendelian randomization[J]. PLoS Genet, 2022, 18(5): e1010166. DOI: 10.1371/journal.pgen.1010166.
[13]	WANG X Q, WANG X L, WANG H K, et al. Association between psoriasis and lung cancer: two-sample Mendelian randomization analyses[J]. BMC Pulm Med, 2023, 23(1): 4. DOI: 10.1186/s12890-022-02297-0.
[14]	LUO G, YAO Y Y, TAO J C, et al. Causal association of sleep disturbances and low back pain: a bidirectional two-sample Mendelian randomization study[J]. Front Neurosci, 2022, 16: 1074605. DOI: 10.3389/fnins.2022.1074605.
[15]	XU J W, ZHANG S Y, TIAN Y, et al. Genetic causal association between iron status and osteoarthritis: a two-sample mendelian randomization[J]. Nutrients, 2022, 14(18): 3683. DOI: 10.3390/nu14183683.
[16]	HUANG G W, CHEN X, CHEN Y B, et al. Causal relationship between type 2 diabetes mellitus and bone mineral density: a Mendelian randomization study in an East Asian population[J]. Osteoporos Int, 2023, 34(10): 1719-1727. doi: 10.1007/s00198-023-06807-6
[17]	LEANZA G, CANNATA F, FARAJ M, et al. Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength[J]. Elife, 2024, 12: RP90437. DOI: 10.7554/eLife.90437.
[18]	KHALID M, PETROIANU G, ADEM A. Advanced glycation end products and diabetes mellitus: mechanisms and perspectives[J]. Biomolecules, 2022, 2(4): 542. DOI: 10.3390/biom12040542.
[19]	AXELSSON K F, LITSNE H, KOUSOULA K, et al. Risk of fracture in adults with type 2 diabetes in Sweden: a national cohort study[J]. PLoS Med, 2023, 20(1): e1004172. DOI: 10.1371/journal.pmed.1004172.
[20]	SCHOUSBOE J T, MORIN S N, KLINE G A, et al. Differential risk of fracture attributable to type 2 diabetes mellitus according to skeletal site[J]. Bone, 2022, 154: 116220. DOI: 10.1016/j.bone.2021.116220.
[21]	SARODNIK C, RASMUSSEN N H, BOURS S P G, et al. The incidence of fractures at various sites in newly treated patients with type 2 diabetes mellitus[J]. Bone Rep, 2022, 17: 101614. DOI: 10.1016/j.bonr.2022.101614.
[22]	HAZELWOOD E, SANDERSON E, TAN V Y, et al. Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis[J]. BMC Med, 2022, 20(1): 125. DOI: 10.1186/s12916-022-02322-3.