Large-scale mediator Mendelian randomization the causal link between gut microbes and chronic graft-versus-host disease risk

被引:0
作者
Chen, Yiyin [1 ]
Yu, Xinghao [1 ,2 ]
Cai, Yiming [1 ]
Jin, Zhou [1 ]
Xu, Yang [1 ,2 ]
机构
[1] Soochow Univ, Affiliated Hosp 1, Jiangsu Inst Hematol, Natl Clin Res Ctr Hematol Dis, Suzhou 215000, Peoples R China
[2] Soochow Univ, Inst Blood & Marrow Transplantat, Collaborat Innovat Ctr Hematol, Suzhou, Peoples R China
关键词
R-PACKAGE; T-CELLS; MORTALITY; NUMBERS; COUNTS;
D O I
10.1016/j.exphem.2025.104794
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Disorders of gut microbiota and immune cells have been observed to be involved in the occurrence of chronic graft-versus-host disease (cGVHD), but their causal connections have yet to be fully understood. This study utilized Mendelian randomization (MR), integrating genome-wide association study (GWAS) meta-analyses from the MiBioGen consortium (microbial taxa), the SardiNIA project (immune traits), and disease data from the Fred Hutchinson Cancer Research Center (FHCRC) cohort to investigate their relationships. The aim was to explore the causal effects of microbiota and immune traits on the incidence of cGVHD, using mediation analysis to identify which immune traits might mediate the effects of microbiota on this condition. The main analysis observed significant causal associations of 3 specific microbial taxa with cGVHD: Lactococcus.id.1851 (odds ratio [OR] = 1.989, 95% confidence interval [CI] = 1.311-3.019, p = 0.001), Ruminiclostridium9.id.11357 (OR = 3.273, 95% CI = 1.604-6.679, p = 0.001), and Intestinimonas. id.2062 (OR = 0.400, 95% CI = 0.230-0.697, p = 0.001). Sensitivity analysis and multivariable MR analysis ruled out possible horizontal pleiotropy and bias. Additionally, 10 immune traits, predominantly covering regulatory T cells (Tregs) and B cells, were identified as influencing cGVHD risk. The two-step mediation MR analysis presented the effect of identified microbial taxa on Tregs and B cells and detailed the pathways through which Intestinimonas impacts cGVHD via CD27 on memory B cells (proportion mediated = 4.2%). Similarly, the role of interactions between Ruminiclostridium9 and effector memory double-negative T cells in mediating cGVHD was quantified, accounting for 9.5% of the total effect. (c) 2025 International Society for Experimental Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
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共 54 条
[1]   A global reference for human genetic variation [J].
Altshuler, David M. ;
Durbin, Richard M. ;
Abecasis, Goncalo R. ;
Bentley, David R. ;
Chakravarti, Aravinda ;
Clark, Andrew G. ;
Donnelly, Peter ;
Eichler, Evan E. ;
Flicek, Paul ;
Gabriel, Stacey B. ;
Gibbs, Richard A. ;
Green, Eric D. ;
Hurles, Matthew E. ;
Knoppers, Bartha M. ;
Korbel, Jan O. ;
Lander, Eric S. ;
Lee, Charles ;
Lehrach, Hans ;
Mardis, Elaine R. ;
Marth, Gabor T. ;
McVean, Gil A. ;
Nickerson, Deborah A. ;
Wang, Jun ;
Wilson, Richard K. ;
Boerwinkle, Eric ;
Doddapaneni, Harsha ;
Han, Yi ;
Korchina, Viktoriya ;
Kovar, Christie ;
Lee, Sandra ;
Muzny, Donna ;
Reid, Jeffrey G. ;
Zhu, Yiming ;
Chang, Yuqi ;
Feng, Qiang ;
Fang, Xiaodong ;
Guo, Xiaosen ;
Jian, Min ;
Jiang, Hui ;
Jin, Xin ;
Lan, Tianming ;
Li, Guoqing ;
Li, Jingxiang ;
Li, Yingrui ;
Liu, Shengmao ;
Liu, Xiao ;
Lu, Yao ;
Ma, Xuedi ;
Tang, Meifang ;
Wang, Bo .
NATURE, 2015, 526 (7571) :68-+
[2]   Actinobacteria: A relevant minority for the maintenance of gut homeostasis [J].
Binda, Cecilia ;
Lopetuso, Loris Riccardo ;
Rizzatti, Gianenrico ;
Gibiino, Giulia ;
Cennamo, Vincenzo ;
Gasbarrini, Antonio .
DIGESTIVE AND LIVER DISEASE, 2018, 50 (05) :421-428
[3]   Altered immune reconstitution of B and T cells precedes the onset of clinical symptoms of chronic graft-versus-host disease and is influenced by the type of onset [J].
Bohmann, E. -M. ;
Fehn, U. ;
Holler, B. ;
Weber, D. ;
Holler, E. ;
Herr, W. ;
Hoffmann, P. ;
Edinger, M. ;
Wolff, D. .
ANNALS OF HEMATOLOGY, 2017, 96 (02) :299-310
[4]   Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator [J].
Bowden, Jack ;
Smith, George Davey ;
Haycock, Philip C. ;
Burgess, Stephen .
GENETIC EPIDEMIOLOGY, 2016, 40 (04) :304-314
[5]   TCRαβ+CD3+CD4-CD8- (double negative) T cells in autoimmunity [J].
Brandt, D. ;
Hedrich, C. M. .
AUTOIMMUNITY REVIEWS, 2018, 17 (04) :422-430
[6]   A review of instrumental variable estimators for Mendelian randomization [J].
Burgess, Stephen ;
Small, Dylan S. ;
Thompson, Simon G. .
STATISTICAL METHODS IN MEDICAL RESEARCH, 2017, 26 (05) :2333-2355
[7]  
Burgess S, 2017, EUR J EPIDEMIOL, V32, P377, DOI 10.1007/s10654-017-0255-x
[8]   Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects [J].
Burgess, Stephen ;
Thompson, Simon G. .
AMERICAN JOURNAL OF EPIDEMIOLOGY, 2015, 181 (04) :251-260
[9]   Mendelian randomisation for mediation analysis: current methods and challenges for implementation [J].
Carter, Alice R. ;
Sanderson, Eleanor ;
Hammerton, Gemma ;
Richmond, Rebecca C. ;
Davey Smith, George ;
Heron, Jon ;
Taylor, Amy E. ;
Davies, Neil M. ;
Howe, Laura D. .
EUROPEAN JOURNAL OF EPIDEMIOLOGY, 2021, 36 (05) :465-478
[10]   Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells [J].
Clark, FJ ;
Gregg, R ;
Piper, K ;
Dunnion, D ;
Freeman, L ;
Griffiths, M ;
Begum, G ;
Mahendra, P ;
Craddock, C ;
Moss, P ;
Chakraverty, R .
BLOOD, 2004, 103 (06) :2410-2416