Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05–1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02–1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01–1.2; P = 0.03], tumor necrosis factor beta (TNF-β) [OR: 1.16; 95% CI: 1.02–1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01–1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-β, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.
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Data availability
We thank the participants and researchers for providing the publicly available summary data used in this study. The data sources and handling of these data are described in the Materials and Methods and in the Supplementary Tables. Further information is available from the corresponding author upon request.
Abbreviations
- DLBCL:
-
Diffuse large B cell lymphoma
- MR:
-
Mendelian randomization
- IVs:
-
Instrumental variables
- GWASs:
-
Genome-wide association studies
- CI:
-
Confidence interval
- IVW:
-
Inverse-variance weighted
- MR-PRESSO:
-
MR-pleiotropy residual sum and outliers
- OR:
-
Odds ratio
- SNPs:
-
Single nucleotide polymorphisms
- CXCL9:
-
CXC chemokine ligand 9
- CXCL10:
-
CXC chemokine ligand 10
- YFS:
-
Young Finns study
- b-NGF:
-
Beta nerve growth factor
- CTACK:
-
Cutaneous T-cell attracting chemokine
- FGFBasic:
-
Basic fibroblast growth factor
- G-CSF:
-
Granulocyte colony-stimulating factor
- GRO-a:
-
Growth-regulated oncogene-a
- HGF:
-
Hepatocyte growth factor
- IFNg:
-
Interferon gamma
- IL:
-
Interleukin
- IP-10:
-
Interferon gamma-induced protein 10
- MCP-1:
-
Monocyte chemotactic protein-1
- MCP-3:
-
Monocyte-specific chemokine 3
- M-CSF:
-
Macrophage colony-stimulating factor
- MIF:
-
Macrophage-migration inhibitory factor
- MIG:
-
Monokine induced by interferon gamma
- MIP-1a:
-
Macrophage inflammatory protein-1a
- MIP-1b:
-
Macrophage inflammatory protein-1b
- PDGFbb:
-
Platelet-derived growth factor BB
- RANTES:
-
Regulated on activation, normal T-cell expressed and secreted
- SCF:
-
Stem cell factor
- SCGFb:
-
Stem cell growth factor beta
- SDF-1a:
-
Stromal cell-derived factor-1 alpha
- TNFα:
-
Tumor necrosis factor alpha
- TNFβ:
-
Tumor necrosis factor beta
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- VEGF:
-
Vascular endothelial growth factor
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Acknowledgements
The authors express their gratitude to the participants and investigators of the FinnGen and YFS, FINRISK studies. We also thank Figdraw (https://www.figdraw.com) for the assistance in model drawing.
Funding
This work was supported by the Youth Project Shaoxing People’s Hospital (Grant Number: 2023YB15), Medical and Health Science and Technology Project of Zhejiang Province (Grant Number: 2023RC107), Department of Health of Zhejiang Province (Grant Number: 2021KY1137), Young Innovative Talents Project of Zhejiang Health Science and Technology Plan (Grant Number: 2022RC078).
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All authors contributed to the study conception and design. Jieni Yu, Chao Xu, and Leihua Fu designed the study, Zhijian Zhang and Lina Ding analyzed and interpreted the data, and drafted the manuscript. Li Hong, Feidan Gao and Jing Jin analyzed and interpreted the data, Jiaping Fu finished the figures, Weiying Feng and Pan Hong revised the manuscript. All author read and approved the final manuscript.
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Yu, J., Fu, L., Zhang, Z. et al. Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study. Clin Exp Med 23, 4585–4595 (2023). https://doi.org/10.1007/s10238-023-01221-y
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DOI: https://doi.org/10.1007/s10238-023-01221-y