基于孟德尔随机化研究分析炎性循环因子与抽动障碍发病风险的关系

张莉莉; 尚莉丽; 崔何晴; 周冰原; 吴安琪

doi:10.11852/zgetbjzz2024-1112

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中国儿童保健杂志 ›› 2025, Vol. 33 ›› Issue (11) : 1261-1269. DOI: 10.11852/zgetbjzz2024-1112

临床研究

基于孟德尔随机化研究分析炎性循环因子与抽动障碍发病风险的关系

张莉莉¹, 尚莉丽^1,2, 崔何晴¹, 周冰原³, 吴安琪³

作者信息 +

Mendelian randomization study on the relationship between inflammatory circulation factors and the risk of tic disorder

ZHANG Lili¹, SHANG Lili^1,2, CUI Heqing¹, ZHOU Bingyuan³, WU Anqi³

Author information +

文章历史 +

摘要

目的探索炎性因子与抽动障碍(TD)之间潜在的因果关系,并以此为靶点探究治疗TD的机制。方法本次孟德尔随机化(MR)研究使用了炎性因子和TD的全基因组关联研究,根据预设的阈值提取与91种炎性因子显著相关的独立遗传位点作为工具变量。主要采用逆方差加权法进行MR分析,根据效应指标优势比(OR)和95%置信区间(95%CI)评估结果。使用留一法、异质性检验、水平基因多效性检验验证结果的稳定性和可靠性。结果分析发现CCL25的P值为0.040(OR=1.331,95%CI:1.014~1.747),CD40的P值为0.040(OR=1.677,95%CI:1.025~2.744),IL-17C的P值为0.013,(OR=0.480,95%CI:0.269~0.858),结果具有统计学意义。结论 CCL25、CD40均能够增加TD的患病风险,IL-17C能够降低TD的患病风险。

Abstract

Objective To explore the potential causal relationship between inflammatory factors and Tourette′s disorder (TD), and to investigate the mechanisms for treating TD based on these findings. Methods This Mendelian randomization (MR) study utilized genome-wide association study (GWAS) data on inflammatory factors and TD. Independent genetic loci significantly associated with 91 inflammatory factors were selected as instrumental variables based on predefined thresholds. The inverse-variance weighted (IVW) method was primarily used for MR analysis, with results evaluated using odds ratios (ORs) and 95% confidence intervals (CIs). Sensitivity analysis, including leave-one-out analysis, heterogeneity testing, and horizontal pleiotropy testing, were conducted to validate the stability and reliability of the results. Results The analysis revealed statistically significant associations for CCL25 (OR＝1.331, 95%CI: 1.014-1.747, P＝0.040), CD40 (OR＝1.677, 95%CI: 1.025-2.744, P=0.040), and IL-17C (OR＝0.480, 95%CI: 0.269-0.858, P＝0.013). Conclusion CCL25 and CD40 are associated with an increased risk of TD, while IL-17C is associated with a reduced risk of TD.

导出引用

张莉莉, 尚莉丽, 崔何晴, 周冰原, 吴安琪. 基于孟德尔随机化研究分析炎性循环因子与抽动障碍发病风险的关系[J]. 中国儿童保健杂志. 2025, 33(11): 1261-1269 https://doi.org/10.11852/zgetbjzz2024-1112

ZHANG Lili, SHANG Lili, CUI Heqing, ZHOU Bingyuan, WU Anqi. Mendelian randomization study on the relationship between inflammatory circulation factors and the risk of tic disorder[J]. Chinese Journal of Child Health Care. 2025, 33(11): 1261-1269 https://doi.org/10.11852/zgetbjzz2024-1112

中图分类号： R179

参考文献

[1] American Psychiatric association. Diagnostic and statistical manual of mental disorders (DSM-5)[M]. Washington DC: American Psychiatric Pub, 2013:81.
[2] Lu C, Wu LQ, Hao H, et al. Clinical efficacy and safety of acupuncture treatment of tic disorder in children: A systematic review and Meta-analysis of 22 randomized controlled trials[J]. Complement Ther Med, 2021, 59(3):102734.
[3] Johnson KA, Worbe Y, Foote KD, et al. Tourette syndrome: Clinical features, pathophysiology, and treatment[J]. Lancet Neurol, 2022, 22(2):147-158.
[4] 常克,徐荣谦,赵进喜,等.抽动障碍病机复杂,调整五脏务求实效[J].环球中医药,2024,17(7): 1320-1323.
Chang K, Xu RQ, Zhao JX, et al. The pathogenesis of tic disorder is complex and adjusting the five zang organs is effective[J]. Global Traditional Chinese Medicine, 2024, 17 (7):1320-1323.(in Chinese)
[5] 刘智胜.儿童抽动障碍诊断要点[J].中国实用儿科杂志,2012,27(7): 481-485.
Liu ZS. Main points in the diagnosis of tic disorders[J]. Chinese Journal of Practical Pediatrics, 2012, 27 (7):481-485.(in Chinese)
[6] 刘应科,崔红,杨健,等.中医药治疗儿科领域临床优势病种的探讨[J].中国实验方剂学杂志,2024,30(15): 224-231.
Liu YK, Cui H, Yang J, et al. Clinical advantages of traditional chinese medicine in treatment of pediatric diseases[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2024, 30 (15):224-231.(in Chinese)
[7] Duan L, Xiao R, Liu S, et al. Causality between cognitive performance and cardiovascular disease: A bidirectional Mendelian randomization study[J]. Gene, 2024, 891 (15):147822.
[8] 何俊慧,朱涪翠,李冬梅,等.基于NF-κB/NLRP3通路探究十大功劳叶提取物对抑郁症大鼠炎症的影响及机制[J].中国实验方剂学杂志,2022,28(17): 67-74.
He JH, Zhu FC, Li DM, et al. Effect of mahonia bealei leaf extract on inflammation in depression of rats via NF-κB/NLRP3 signaling pathway[J].Chinese Journal of Experimental Traditional Medical Formulae, 2022, 28 (17):67-74.(in Chinese)
[9] 何俊慧,韦洁,李冬梅,等.基于TLR4/NF-κB通路探讨蛤蚧提取物对利血平诱导抑郁大鼠神经炎症的影响[J].中国实验方剂学杂志,2021,27(9): 56-62.
He JH, Wei J, Li DM, et al. Effect ofgecko extract on neuroinflammation in rats with reserpine induced depression via TLR4/NF-κB pathway[J].Chinese Journal of Experimental Traditional Medical Formulae, 2021, 27 (9):56-62.(in Chinese)
[10] 唐仕浩,张堃,刘春贵,等.孟德尔随机化探究细胞因子与深静脉血栓的因果效应[J].现代预防医学,2021,48(4): 759-764.
Tang SH, Zhang K, Liu CG, et al. Causal association between cytokines and deep vein thrombosis based on mendelian randomization[J]. Modern Preventive Medicine, 2021, 48 (4):759-764.(in Chinese)
[11] Fu C, Chen Y, Xu W, et al. Exploring the causal relationship between inflammatory cytokines and migraine: A bidirectional, two sample mendelian randomization study[J]. Sci Rep, 2023, 13(1):19394.
[12] Alayash Z, Baumeister SE, Holtfreter B, et al. Complement c3 as a potential drug target in periodontitis: Evidence from the cis-mendelian randomization approach[J]. J Clin Periodontol, 2024, 51(2):127-134.
[13] Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets[J]. Nat Immunol, 2023, 24(9):1540-1551.
[14] Xiao R, Dong L, Xie B, et al. A mendelian randomization study: Physical activities and chronic kidney disease[J]. Ren Fail, 2024, 46(1):2295011.
[15] 杨敬言,马涉,黄仁俊,等.基于孟德尔随机化分析躯干及下肢脂肪量与椎间盘退变的因果关系[J].中国组织工程研究,2024,28(35): 5688-5694.
Yang JY, Ma S, Huang RJ, et al. Causal relationship between trunk and lower limb fat mass and intervertebral disc degeneration based on a Mendelian randomization analysis[J]. J Clin Rehabil Tis Eng Res, 2024, 28 (35):5688-5694.(in Chinese)
[16] 崔鹏源,李贵平.孟德尔随机化法探究新生儿高胆红素血症与抽动障碍的因果关联[J].中国儿童保健杂志,2024,32(10): 1116-1121.
Cui PY, Li GP. Causal relationship between neonatalhy perbilirubinemia and tic disorder by Mendelian randomization[J]. Chin J Child Health Care, 2024, 32 (10):1116-1121.(in Chinese)
[17] Cao Z, Wu Y, Li Q, et al. A causal relationship between childhood obesity and risk of osteoarthritis:Results from a two-sample Mendelian randomization analysis[J]. Ann Med, 2022, 54(1):1636-1645.
[18] Mao R, Yu Q, Li J. The causal relationship between gut microbiota and inflammatory dermatoses: A Mendelian randomization study[J]. Front Immunol, 2023, 14:1231848.
[19] Ding M, Zhang Z, Chen Z, et al. Association between periodontitis and breast cancer: Two-sample Mendelian randomization study[J]. Clin Oral Investig, 2023, 27(6):2843-2849.
[20] 郑治民,孙昊,赵婷婷,等.基于全基因组关联研究数据分析肠道菌群与矮小症的因果关系[J].中国儿童保健杂志,2024,32(11): 1201-1205,1211.
Zheng ZM, Sun H, Zhao TT, et al. Causal relationship between gut microbiota and short stature based on genomewide association study data[J].Chin J Child Health Care, 2024, 32(11):4417-4421,4452.(in Chinese)
[21] 隆丽芳,魏琳,王秋婷,等.细胞间黏附分子5与神经免疫系统疾病的孟德尔随机化研究[J].现代预防医学,2023,50(24): 4417-4421,4452.
Long LF, Wei L, Wang QT, et al. Intercellular adhesion molecule 5 and neuroimmune system diseases: A Mendelian randomization study[J]. Modern Preventive Medicine, 2023, 50(24):4417-4421,4452.(in Chinese)
[22] Chen S, Zhang W, Zheng Z, et al. Unraveling genetic causality between type 2 diabetes and pulmonary tuberculosis on the basis of Mendelian randomization[J]. Diabetol Metab Syndr, 2023, 15(1):228.
[23] 杨振国,王蕾.两样本孟德尔随机化:肠道菌群与偏头痛[J].现代预防医学,2023,50(20): 3656-3662.
Yang ZG, Wang L. Two sample Mendelian randomization: intestinal flora and migraine[J].Modern Preventive Medicine, 2023, 50(20):3656-3662.(in Chinese)
[24] 赵利平,胡晓红,李中原.儿童抽动障碍发病机制研究进展[J].发育医学电子杂志,2024,12(3): 224-228.
Zhao LP, Hu XH, Li ZY, et al. Research progress on pathogenesis of tic disorder in children[J]. Journal of Developmental Medicine(Electronic Version), 2024, 12 (3):224-228.(in Chinese)
[25] Prinz M, Jung S, Priller J. Microglia biology: One century of evolving concepts[J]. Cell, 2019, 179(2):292-311.
[26] Han VX, Patel S, Jones HF, et al. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders[J]. Nat Rev Neurol, 2021, 17(9):564-579.
[27] 周红亮,陈洁,章建英,等.儿童抽动障碍与肠道菌群及炎症反应免疫指标相关性研究[J].安徽医药,2024,28(6): 1208-1211.
Zhou HL, Chen J, Zhang JY, et al. Correlation between tic disorder and intestinal flora, inflammatory response and immune indexes in children[J]. Anhui Med Pharm J, 2024, 28 (6):1208-1211.(in Chinese)
[28] 毕玲美.托吡酯治疗儿童抽动障碍的疗效及其对血清IL-6、TNF-α水平的影响[J].中国处方药,2021,19(6): 94-96.
Bi LM. Efficacy of topiramate in the treatment of children with tic disorder and its effect on serum IL-6 and TNF-α levels[J]. Journal of China Prescription Drug, 2021, 48(4):759-764.(in Chinese)
[29] 张金剑.托吡酯对抽动障碍患儿血清炎症因子水平的影响及疗效观察[J].药物流行病学杂志,2013,22(8): 417-419.
Zhang JJ. Effect of topiramate on serum inflammatory factors in children with tic disorder and its curative effect observation[J]. Chinese Journal of Pharmacoepidemiology, 2013, 22(8):417-419.(in Chinese)
[30] Chi S, Mok YE, Kang J, et al. Cytokine levels reflect tic symptoms more prominently during mild phases[J]. BMC Neurosci, 2023, 24(1):57.
[31] Vicari AP, Figueroa DJ, Hedrick JA, et al. TECK: A novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development[J]. Immunity, 1997, 7(2):291-301.
[32] Wu X, Sun M, Yang Z, et al. The roles of CCR9/CCL25 in inflammation and inflammation associated diseases[J]. Front Cell Dev Biol, 2021, 19(9):686548.
[33] Martino D, Zis P, Buttiglione M. The role of immune mechanisms in tourette syndrome[J]. Brain Res, 2015, 1617:126-143.
[34] 冯雪英,衣明纪,侯建文.抽动障碍儿童免疫状况及预防接种问题[J].中国儿童保健杂志,2013,21(1):62-64.
Feng XY, Yi MJ, Hou JW, et al. Immune status and vaccination problems of children with tic disorder[J]. Chin J Child Health Care, 2013, 21(1):62-64.(in Chinese)
[35] Parker-Athill EC, Ehrhart J, Tan J, et al. Cytokine correlations in youth with tic disorders[J]. J Child Adolesc Psychopharmaco, 2015, 25(1):86-92.
[36] Gossens K, Naus S, Corbel SY, et al. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P controlled expression of thymic p-selectin/CCL25[J]. J Exp Med, 2009, 206(4):761-778.
[37] 匡桂芳,蒋玉红,傅平,等.巨细胞病毒DNA含量及T淋巴细胞亚群变化与抽动障碍发病的关系[J].中国行为医学科学, 2005, 14(3):50-51.
Kuang GF, Jiang YH, Fu P, et al. Clinical significance of HCMV-DNA detection and T lymphocyte subgroups in children with tic disorder[J]. Chinese Journal of Behavioral Medical Science, 2005, 14(3):50-51.(in Chinese)
[38] Chen K, Huang J, Gong W, et al. CD40/CD40L dyad in the inflammatory and immune responses in the central nervous system[J]. Cell Mol Immunol, 2006, 3(3):163-169.
[39] Senhaji N, Kojok K, Darif Y, et al. The contribution of CD40/CD40L axis in inflammatory bowel disease: An update[J]. Front Immunol, 2015, 6:529.
[40] 贺晴,张永婷,边玉露,等.中药、复方及非药物疗法治疗抽动障碍相关信号通路作用机制的研究进展[J/OL].中药药理与临床,1-23[2024-09-02].doi:10.13412/j.cnki.zyyl.20240420.002.
He Q, Zhang YT,Bian YL, et al. Research progress in signaling pathways involved in management of tic disorder with traditional Chinese medicine and non-drug therapies[J/OL]. Pharmacology and Clinics of Chinese Materia Medica, 1-23[2024-09-02]. doi:10.13412/j.cnki.zyyl.20240420.002.(in Chinese)
[41] Long H, Ruan J, Zhang M, et al. Gastrodin alleviates tourette syndrome via Nrf-2/HO-1/HMGB1/NF-кB pathway[J]. J Biochem Mol Toxicol, 2019, 33(10):e22389
[42] Long H, Wang C, Ruan J, et al. Gastrodin attenuates neuroinflammation in DOI induce tourette syndrome in rats[J]. J Biochem Mol Toxicol, 2019, 33(5):e22302.
[43] Long H, Ruan J, Zhang M, et al. Rhynchophylline attenuates tourette syndrome via BDNF/NF-κB pathway in vivo and in vitro[J]. Neurotox Res, 2019, 36(4):756-763.
[44] Leu WJ,Chen JC,Guh JH. Extract from plectranthus amboinicus inhibit maturation and release of interleukin 1beta through inhibition of NF-κB nuclear translocation and NLRP3 inflammasome activation[J]. Front Pharmacol, 2019, 10:573.
[45] Jurcau A, Simion A. Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: From pathophysiology to therapeutic strategies[J]. Int J Mol Sci, 2021, 23(1):14.
[46] Li H, Chen J, Huang A, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family[J]. Proc Natl Acad Sci U S A, 2000, 97(2):773-778.
[47] Swedik S, Madola A, Levine A. IL-17C in human mucosal immunity: More than just a middle child[J]. Cytokine, 2021, 146:155641.
[48] 常虹,唐烨霞,王紫玄,等.针刺联合小儿推拿对抽动障碍患儿肠道菌群的影响[J].中国针灸,2023,43(5): 509-516.
Chang H, Tang YX, Wang ZX, et al. Effect of acupuncture combined with infantile tuina on intestinal flora in children with tic disorders[J]. Chin Acup Moxib, 2023, 43 (5):509-516.(in Chinese)
[49] Mondot S, Lepage P, Seksik P, et al. Structural robustness of the gut mucosal microbiota is associated with crohn′s disease remission after surgery[J]. Gut, 2016, 65(6):954-962.
[50] Liu P, Jiang Y, Gu S, et al. Metagenome-wide association study of gut microbiome revealed potential microbial marker set for diagnosis of pediatric myasthenia gravis[J]. BMC Med, 2021, 19(1):159.
[51] Ramirez-Carrozzi V, Sambandam A, Luis E, et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner[J]. Nat Immunol, 2011, 12(12):1159-1166.
[52] Johnston A, Fritz Y, Dawes SM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation[J]. J Immunol, 2013, 190(5):2252-2262.
[53] Tanaka S, Nagashima H, Cruz M, et al. Interleukin-17C in human helicobacter pylori gastritis[J]. Infect Immun, 2017, 85(10):e00389-17.
[54] Im E, Jung J, Rhee SH. Toll-like receptor 5 engagement induces interleukin-17C expression in intestinal epithelial cells[J]. J Interferon Cytokine Res, 2012, 32(12):583-591.
[55] Yeon SM, Lee JH, Kang D, et al. A cytokine study of pediatric Tourette′s disorder without obsessive compulsive disorder[J]. Psychiatry Res, 2017, 247:90-96.