基于孟德尔随机化方法探讨炎症性肠病与骨质疏松性骨折的因果关系

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Abstract Objective： To investigate the causal relationship between inflammatory bowel disease and osteoporotic fracture by using the two-sample Mendelian randomization (MR) method. Methods: The pooled data from GenomeWide Association Studies (GWAS) were analyzed. Samples from Crohn′s disease and ulcerative colitis were selected for further analysis, where GWAS summary data for Crohn′s disease and ulcerative colitis were obtained from the European IEU database, 20 883 for Crohn′s disease, 47 745 for ulcerative colitis, and GWAS summary data for osteoporotic fractures from the FinnGen database, 173 619. Single nucleotide polymorphisms (SNPs), which are closely associated with Crohn′s disease and ulcerative colitis, were used as instrumental variables (IVs), and the inverse variance weighting method (IVW), the MR-Egger regression method, the Weighted Median method (WME), Simple Mode method and the Weighted Mode method were used to evaluate the causal relationship by means of odds ratio (OR). The Cochran Q heterogeneity test was performed by IVW and MR-Egger method, horizontal pleiotropy analysis by MR_pleiotropy_test function and MR PRESSO pleiotropy test, sensitivity analysis by MR_leaveoneout_plot function, and F values were calculated to evaluate the presence of weak IVs bias. Results: A total of 52 SNPs closely related to Crohn′s disease were obtained as IVs, IVW result ［OR(95%CI): 1.12(1.03-1.22), P=0.006］, WME result ［OR(95%CI) 1.15(1.01-1.32), P=0.02］, MREgger results ［OR(95%CI) 1.16(0.94-1.44), P=0.15］. Simple Mode results ［OR(95%CI): 1.15(0.88-1.50), P=0.28］ and Weighted Mode results ［OR(95%CI): 1.16(0.97-1.39), P=0.10］ suggested a positive causal relationship between Crohn′s disease and osteoporotic fracture. In total, 88 SNPs closely associated with ulcerative colitis were obtained as IVs, IVW result ［OR(95%CI) 1.15(1.03-1.28), P=0.009］, MREgger result ［OR(95%CI): 1.35(1.03-1.75), P=0.02］, WME result ［OR(95%CI): 1.18(1.01-1.37), P=0.02］, Simple Mode result ［OR(95%CI): 1.15(0.86-1.55), P=0.32］ and Weighted Mode results ［OR(95%CI): 1.19(0.96-1.47), P=0.10］ suggested a positive causal relationship between ulcerative colitis and osteoporotic fracture. The results of the heterogeneity test in Crohn′s disease-osteoporotic fractures were P=0.55 and P=0.52, respectively, suggesting the absence of heterogeneity. The MR_pleiotropy_test function result was P=0.69, and the MR PRESSO method result was P=0.55, indicating the absence of pleiotropy, and the sensitivity analysis showed stable results. The heterogeneity tests of ulcerative colitis-osteoporotic fractures were P=0.23 and P=0.25, respectively, suggesting the absence of heterogeneity. The MR_pleiotropy_test function result was P=0.20, and the MR PRESSO method result was P=0.24, indicating the absence of pleiotropy, and the sensitivity analysis showed stable results. All F values were greater than 10, suggesting that there was no weak IVs bias. Conclusion: Inflammatory bowel disease may increase the risk of osteoporotic fractures.

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Received: 11 July 2023

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	CHEN Shangtong1
	CHEN Yueping2
	SONG Shilei1
	HUANG Chuanhong1

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CHEN Shangtong1,CHEN Yueping2,SONG Shilei1等. The causal relationship between inflammatory bowel disease and osteoporosis fracture based on a Mendelian randomization

[J]. Journal of Jiangsu University(Medicine Edition), 2024, 24(01): 67-73.

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http://zzs.ujs.edu.cn/xbyxb/EN/ OR http://zzs.ujs.edu.cn/xbyxb/EN/Y2024/V24/I01/67

［1］詹红生, 章振林. 中成药治疗骨质疏松症临床应用指南（2021年）［J］. 中国中西医结合杂志, 2022, 42(4): 393-404.

［2］中华医学会骨质疏松和骨矿盐疾病分会, 章振林. 原发性骨质疏松症诊疗指南（2022）［J］. 中国全科医学, 2023, 26(14): 1671-1691.

［3］程鉥泺, 陶雪芬, 赵荣, 等. TLR4/NFκB通路与骨质疏松症关系的研究进展［J］. 中国骨质疏松杂志, 2023, 29(7): 1037-1042.

［4］毛银枫, 崔松香, 华臻, 等. 基于网络药理学探究黄芪白术药对治疗骨质疏松性骨折的作用机制［J］. 江苏大学学报(医学版), 2022, 32(1): 13-17.

［5］Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease［J］. Gastroenterology, 2017, 152(2): 313-321.e2.

［6］余静, 徐钧, 胡华. 克罗恩病患者骨密度、骨代谢以及钙、镁、锌和磷水平特点分析［J］. 中国骨质疏松杂志, 2019, 25(4): 509-511, 522.

［7］冉艳, 米琛, 厉英超. 炎症性肠病患者骨质流失的机制和治疗前景［J］. 胃肠病学, 2021, 26(10): 631-635.

［8］Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology［J］. Stat Med, 2008, 27(8): 1133-1163.

［9］Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations［J］. Nat Genet, 2015, 47(9): 979-986.

［10］ByrskaBishop M, Evani US, Zhao X. Highcoverage wholegenome sequencing of the expanded 1000 Genomes Project cohort including 602 trios［J］. Cell, 2022, 185(18): 3426-3440.e19.

［11］黄国鑫, 陈霞丽, 裴斌. 孟德尔随机化探索骨密度与膝关节骨性关节炎的因果关联［J］. 中国骨质疏松杂志, 2023, 29(4): 512-517.

［12］Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases［J］. Nat Genet, 2018, 50(5): 693-698.

［13］Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression［J］. Int J Epidemiol, 2015, 44(2): 512-525.

［14］Lewandowski K, Kaniewska M, Wicek M, et al. Risk factors for osteoporosis among patients with inflammatory bowel disease—do we already know everything?［J］. Nutrients, 2023, 15(5): 1151.

［15］Ratajczak AE, SzymczakTomczak A, Michalak M, et al. Associations between vitamin D, bone mineral density, and the course of inflammatory bowel disease in Polish patients［J］. Pol Arch Intern Med, 2022, 132(12): 16329.

［16］Saadah OI, Annese V, Mosli MH. Prevalence and predictors of reduced bone density in child and adolescent patients with Crohn′s disease［J］. J Clin Densitom, 2021, 24(2): 252-258.

［17］Jin HY, Lim JS, Lee Y, et al. Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease［J］. BMC Pediatr, 2021, 21(1): 35.

［18］Targownik LE, Bernstein CN, Nugent Z, et al. Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis［J］. Clin Gastroenterol Hepatol, 2013, 11(3): 278-285.

［19］Hidalgo DF, Boonpheng B, Phemister J, et al. Inflammatory bowel disease and risk of osteoporotic fractures: a metaanalysis［J］. Cureus, 2019, 11(9): e5810.

［20］Bartko J, Reichardt B, Kocijan R, et al. Inflammatory bowel disease: a nationwide study of hip fracture and mortality risk after hip fracture［J］. J Crohns Colitis, 2020, 14: 1256-1263.

［21］Wong SC, CattoSmith AG, Zacharin M. Pathological fractures in paediatric patients with inflammatory bowel disease［J］. Eur J Pediatr, 2014, 173: 141-151.

［22］Felice C, Dal Buono A, Gabbiadini R, et al. Cytokines in spondyloarthritis and inflammatory bowel diseases: from pathogenesis to therapeutic implications［J］. Int J Mol Sci, 2023, 24(4): 3957.

［23］Remily EA, Sax OC, Douglas SJ, et al. Inflammatory bowel disease is associated with increased complications after total knee arthroplasty［J］. Knee, 2023, 40: 313-318.

［24］王世浩, 付赛, 赵宇, 等. 两样本孟德尔随机化研究肾功能对骨质疏松症的因果关系［J］. 现代预防医学, 2022, 49(9): 1537-1542,1589.

［25］Kuo TR, Chen CH. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives［J］. Biomark Res, 2017, 5: 18.

［26］雷鹏蛟, 王亮, 马远征, 等. 微量元素与骨质疏松的相关性研究进展［J］. 中国骨质疏松杂志, 2014, 20(3): 343-346.

［27］Vernia F, Burrelli Scotti G, Bertetti NS, et al. Low vitamin K and vitamin D dietary intake in patients with inflammatory bowel diseases［J］. Nutrients, 2023, 15(7): 1678.

［28］Barbalho SM, Goulart RA, Gasparini RG. Associations between inflammatory bowel diseases and vitamin D［J］. Crit Rev Food Sci Nutr, 2019, 59(8): 1347-1356.

［29］Paganelli M, Albanese C, Borrelli O, et al. Inflammation is the main determinant of low bone mineral density in pediatric inflammatory bowel disease［J］. Inflamm Bowel Dis, 2007, 13(4): 416-423.

［30］de Lange KM, Moutsianas L, Lee JC, et al. Genomewide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease［J］. Nat Genet, 2017, 49(2): 256-261.

［31］Astle WJ, Elding H, Jiang T, et al. The allelic landscape of human blood cell trait variation and links to common complex disease［J］. Cell, 2016, 167(5): 1415-1429.e19.

［32］Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention［J］. Nat Rev Drug Discov, 2012, 11(3): 234-250.

［33］Guo J, Wang F, Hu Y, et al. Exosomebased bonetargeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases［J］. Cell Rep Med, 2023, 4(1): 100881.